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Posts Tagged ‘National Institutes of Health’

 

Reporter: Aviva Lev-Ari, PhD, RN

Stem cells create new heart cells in baby mice, but not in adults, study shows
stem cell growth

Kotlikoff Lab
The picture on the left shows green c-kit+ precursor stem cells within an infarct (lower right) in a three-day old mouse. These cells are becoming new myocytes and also new vessels. On the right is another image of a heart taken after three months showing a small residual scar (on bottom) remaining from what was an infarct, and new myocytes (red areas) throughout the region.

In a two-day-old mouse, a heart attack causes active stem cells to grow new heart cells; a few months later, the heart is mostly repaired. But in an adult mouse, recovery from such an attack leads to classic after-effects: scar tissue, permanent loss of function and life-threatening arrhythmias.

A new study by Cornell and University of Bonn researchers found that stem cells did not create new heart cells in adult mice after a heart attack, settling a decades-old controversy about whether stem cells play a role in the recovery of the adult mammalian heart following infarction — the leading cause of sudden death in the developed world — where heart tissue dies due to artery blockage.

“If you did have fully capable stem cells in adults, why are there no new heart cells after an infarct? And is this due to the lack of stem cells or due to something special about the infarct that inhibits stem cells from forming new heart cells?” asked Michael Kotlikoff, the Austin O. Hooey Dean of Cornell’s College of Veterinary Medicine, and senior author of the paper appearing Aug. 29 in the Proceedings of the National Academy of Sciences.

Beating heart cells

This movie shows beating heart cells in culture that originated as stem cells (look closely around the center of the frame). The researchers used a mouse model where heart cells fluoresced red and undifferentiated stem cells fluoresced green. All of the cells shown in the movie were green at the time of culture and they turn red after they become heart cells. There were no red cells to start, indicating that the origin of the beating red cells was green stem cells. Watch video

Co-author Michelle Steffey, a small-animal surgeon in Cornell’s veterinary college, developed a procedure to infarct a neonatal mouse heart that is only one-tenth-of-an-inch wide. “It was a tour-de-force technically to infarct and recover those baby mice,” said Kotlikoff.

The baby mice grew new heart cells and almost completely recovered from infarction, proving that the infarction did not inhibit stem cells from growing new heart cells. The same procedure was carried out on adult mice and no new heart cells formed, confirming that adults do not have the requisite stem cells to create new heart cells, called myocytes, though new blood vessel cells were created.

To track the stem cells, Kotlikoff and colleagues used a mouse model they developed in which cells fluoresce green when the stem cell marker c-kit is present. In the experiment, after infarction, cells with the c-kit marker fluoresced green in neonatal and adult mice.

“In looking at the adult responses, we were able to prove that the c-kit-marked cells do not form heart cells, but form all of the new blood vessels within the infarct,” said Kotlikoff. The stem cells found in the adult heart “have lost the ability to become heart cells,” he said. It is known that developmentally single stem cells differentiate into all tissues at the start of life, but over time these cells become “developmentally restricted” or specialized to form only certain tissues, he added.

The study also showed for the first time that vessel stem cells in the adult heart originate there and are not recruited from bone marrow, as has been reported. Those reports have justified a controversial procedure in which bone marrow cells are injected into patients with infarctions.

Finally, the study settles the question of whether new heart cells in a neonatal mouse come from undifferentiated stem cells or from pre-existing heart cells that divide. To answer the question, the researchers used another mouse model where heart cells fluoresced red and undifferentiated stem cells fluoresced green. These two cell types were separated. The researchers found that the green stem cells that had moved into the infarct formed beating red heart cells in culture, proving that the stem cells had become heart cells.

Sophie Jesty, an associate professor and resident in cardiology at Cornell’s College of Veterinary Medicine, is the paper’s lead author. Researchers at the University of Bonn analyzed the mice to understand and quantify new myocyte formation.

The study was funded by the National Institutes of Health, New York State Stem Cell Science and the European Union Seventh Framework Programme.

 

 

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Reporter: Aviva Lev-Ari, PhD, RN

The information below is posted on our Scientific Web Site in solidarity with all the Young Life Sciences Scientists in the US, Canada and around the Globe regarding the discrepancy in the marketplace between high supply of highly qualified young scientists and the low demand for their talent by Academia and by the Pharmaceutical and Biotech Industries as evidenced by few jobs for that valuable talent.

The matter has been address by the NIH and was reported in my post on June 27, 2012

Picturing US-Trained PhDs’ Paths and Pharmaceutical Industry’s Crisis of Productivity: Partnerships between Industry and Academia

http://pharmaceuticalintelligence.com/2012/06/27/picturing-us-trained-phds-paths-pharmaceutical-industrys-crisis-of-productivity-partnerships-between-industry-and-academia/

Related matters on that subject are addressed in the following Posts by Dr. Jonathan Thon

Dr. Thon holds joint appointments within the hematology division at Brigham and Women’s Hospital, and Harvard Medical School in Boston, and is an American Society of Hematology Scholar.

The truly bleak job prospects for young scientists in the life sciences

Posted on July 30, 2012 by Jonathan Thon

The following is my response to a letter from Canada’s federal minister of health, Leona Aglukkaq, who was in turn responding to an earlier letter from me:

Honourable Leona Aglukkaq,

Thank you first and foremost for taking the time to respond to my letter on February 7, 2012, regarding the lack of opportunity for early-career scientists in Canada (see the health minister’s response here). While the Canadian Institutes of Health Research (CIHR) is taking positive steps to meet its stated goals of attracting and retaining the best researchers, the Canadian government is failing to acknowledge how truly bleak the job prospects for young scientists are in the life sciences. While resources will always be limiting, the government needs to appreciate that current federal investment in biomedical science is insufficient to maintain the present rate of scientific advancement and falls short of supporting a sustainable pipeline of talented new health researchers. What’s more, this country’s overabundance of PhDs has kept postdoctoral salaries at a rate of $38,000 per year, which is shockingly low when one considers that a four-year undergraduate degree and five-year graduate program are required to fill the role. Worse still, it has extended postdoctoral fellowships (considered neither “student” nor “faculty” positions in Canada) to between four and eight years, creating a temporary “holding pattern” from which most young scientists ultimately transition to other careers.

If Canada is not prepared to make the necessary investment in academic biomedical research, universities must not be permitted to continue to push PhD students and postdoctoral fellows through the present system blindly, with complete disregard to the lack of academic career opportunities that await them. By failing to adapt to current labour market trends, the Canadian people are investing a significant amount of time and money into training highly-educated life scientists to take up positions that simply do not exist, forcing them into under-employment in the private sector. Not only does this represent a terrible return on investment, but it is stunting economic growth. The number of graduate students being trained for academic science positions that 80 percent of them will never fill needs to decrease significantly and the focus needs to shift from academic professorships to alternative professions as support scientists and consultants in neighbouring industries including medicine, finance, teaching and law.

Recently, both the U.S. National Academies and the National Institutes of Health’s Biomedical Workforce issued reports exhorting universities to “improve the capacity of graduate programs to attract talented students by addressing issues such as attrition rates, time-to-degree, funding, and alignment with both student career opportunities and national interests.” To accomplish this, the U.S. National Academies recommend that institutions “restructure doctoral education to […] shorten time-to-degree and strengthen the preparation of graduates for careers both in and beyond the academy.” The NIH concurred, citing the need to “involve relevant employers in the public and private sector in designing and training paths for students.” Among the reforms called for are:

  • Information and guidance about career opportunities and training in skills relevant to non-academic jobs to be provided to all graduate students and post-doctoral fellows on fellowships or principal investigator grants as normal parts of their programs.
  • Limitations to the period any individual can spend as a graduate student of post-doctoral fellow, which must be covered in its entirety under “any combination of training grants, fellowships and research project grants.”
  • Increasing the proportion of graduate students and post-doctoral fellows that receive support through fellowships and training grants versus faculty research grants, to shift the focus from the principal investigators’ labour needs to young scientists’ professional development. The report emphasizes that the overall number of young scientists supported should not increase.
  • Institutional tracking over time of career outcomes for all their graduate students and post-doctoral fellows, which should be made publicly available.

The last two recommendations are perhaps the most important and I have separated them here for added emphasis.

  • To improve career opportunities and limit the overproduction of transient trainees, labs should replace many of their post-doctoral fellow slots with permanent staff scientist positions.
  • Post-doctoral pay and benefits must improve. The Biomedical Workforce proposes implementing a starting salary of $42,000 (which I still consider to be a discouraging return on the increasingly lengthening 5-year investment necessary to earn a PhD), with a “large jump between [post-doctoral] years 3 and 4” intended “to incentivize principal investigators to move fellows to permanent positions.” Given the current state of academic science, the Biomedical Workforce felt it necessary to add that “all NIH-supported postdoctoral researchers on any form of support (training grants, fellowships, or research project grants) [should] receive benefits that are comparable to other employees at the institution,” including paid vacation, parental leave, healthcare, and retirement plans.

The government of Canada has done little to acknowledge and less to address the current overabundance of highly-trained young PhD scientists in low-paying dead-end jobs whose expertise will ultimately (after a significant period of re-training) be better served in other industries. While the CIHR’s efforts to improve current funding practices are necessary, they will not prove sufficient to resolve this issue. The current approach to training scientists and moving them through the labour force is frighteningly inefficient. Training more research scientists than we have the funds to support is not the solution – it is the problem. Acknowledging that we are facing a crisis and implementing the aforementioned recommendations will dramatically improve working conditions for young scientists while curbing inefficiencies in our labour market that are serving to limit economic growth.

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In a concerted effort to practice what I preach, I write often to the Office of the Prime Minister to highlight issues facing early-career scientists in Canada. To their credit, I always receive a response. Below is a transcript of the most recent letter I received from the Minister of Health, Leona Aglukkaq. Please see ‘Bring home the scientific troops’ to review previous transcripts.

Dear Dr. Thon:

The office of the Prime Minister has forwarded to me a copy of your correspondence of February 7, 2012, concerning opportunities for young scientists in Canada.

The Canadian Institutes of Health Research (CIHR) recognizes the role that new and early career investigators play in creating a sustainable foundation for Canadian health research. In its second strategic plan entitled Health Research Roadmap: Creating innovative research for better health and health care, the CIHR stated its intention to build capacity to attract and retain the best researchers by working with partners at all levels, including teaching hospitals, other federal funding agencies and federal departments. This will involve, among other things, ensuring that sufficient operational support is provided by rectifying the inconsistencies in postdoctoral funding and reviewing the level and form of financial assistance provided.

As part of the CIHR’s commitment to ensuring the long-term sustainability of its contribution to the Canadian health research enterprise, the CIHR has also initiated a process to design a new open suite of programs and peer review system. The new design responds to concerns such as yours from the health community that we need to be providing more support for new and early career investigators.

In the new open suite of programs, the CIHR is considering specific support to new and early career investigators with excellent training and early career productivity to ensure that these researchers have an opportunity to build promising programs of research and knowledge translation. In a new scheme that focuses on projects, the CIHR is considering giving priority in the first stage of review to the quality of the idea with limited information about the track record of the applicant. This would remove some of the biases or barriers (real or perceived) for new and early career investigators.

The CIHR’s direct training programs are not changing as part of this process and will continue to be a part of the CIHR’s strategy to support a sustainable pipeline of talented new health researchers into the health research enterprise.

It should also be noted that the CIHR’s Strategy for Patient Oriented Research also has a focus on developing the talent pool for clinical research in Canada. You can follow the development of this important strategy on their website athttp://www.cihr-irsc.gc.ca.

With regard to your concern about the low levels of successful applications in the CIHR’s Open Operating Grants Program, it should be noted that in February 2008, the CIHR pledged to create and maintain a stable Open Operating Grant Program. This included a commitment to fund at least 400 new grants per competition (800 per year). This commitment will be maintained with the new program structure.

The CIHR currently funds some 14,000 researchers and trainees. In designing the new funding program, the CIHR’s intent is to continue supporting a similar number of investigators and trainees. Furthermore, the CIHR is committed to ensuring that approximately 70 percent of the grants and awards budget continues to be allocated to support investigator-initiated research.

I appreciate having had this opportunity to respond to your concerns.

Sincerely

Leona Aglukkaq

c.c. Office of the Prime Minister

I will be responding to Ms. Aglukkaq’s letter in my following post – and I encourage you to do the same. You can contact the Honourable Leona Aglukkaq at:

House of Commons
458 Confederation Building
Ottawa, Ontario
K1A 0A6

Tel: (613) 992-2848
Fax: (613) 996-9764
Email: Leona.Aglukkaq@parl.gc.ca

The research bottleneck – flying blind

Posted on June 25, 2012 by Jonathan Thon

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The Bridges to Independence report (NRC, 2005) reveals that the number of PhD-trained life scientists in the United States ages 35 and younger increased by 59 percent between 1993 and 2001 while the number of these scientists in tenure-track positions increased by only 7 percent. At research institutions this number decreased by 12 percent over the same period of time. Studies by Michael S. Teitelbaum (Research funding: structural disequilibria in biomedical research. Science 321, 644-645. 2008) and Cyranoski, D. et al. (The PhD factory: the world is producing more PhDs than ever before. Is it time to stop? Nature 472, 276-279. 2011) support these observations and show that the supply-demand gap continues to grow.

Studies from the National Association of Teachers in Further and Higher Education, the British university and college lecturer’s union, and the BETT Report, published in June 1999 by the Independent Review of Higher Education, Pay and Conditions, paint a similar picture for scientists in the United Kingdom and suggest a similar situation worldwide. With limited employment opportunities in academia as it is (Improving graduate education to support a branching career pipeline: Recommendations based on a survey of doctoral students in the basic biomedical sciences. 2011.), this statistic reflects a bad situation only getting worse.

To better assess the magnitude of this problem and compel academic institutions to address it, I suggest federal departments require universities to submit a detailed account of the placement histories of their recent graduates, which should be made available freely online. Another statistic worth tracking is the percentage of graduate students or research fellows training under principal investigators that now support independent research programs of their own. Comparing these figures to research investment practices that have traditionally focused on graduate and postdoctoral funding while avoiding the larger issue of subsequent employment should let us measure the effect these policies have on the knowledge market and provide the impetus to change them. At the very least, it would let prospective scientists know what they were getting into.

Because I am not the first to suggest that dissatisfaction later in their career has less cogency if students investing in a bioscience research career when they choose graduate training are made aware of the risks pursuant, a recent NRC Committee on Trends in the Early Career Patterns of Life Scientists recommended in 1998 “that accurate and up-to-date information on career prospects … and career outcome information … be made widely available to students and faculty. Every life science department receiving federal funding for research training should be required to provide its prospective graduate students specific information regarding all pre-doctoral students enrolled in the graduate program during the preceding 10 years.”

While this is a clear step in the right direction, a recent survey of 10 leading biology departments (experimental group) and professional schools (control group) in the United States concerning the information available to students considering a career in the biosciences showed striking differences between the two groups (Careers and Rewards in Bio Sciences: the disconnect between scientific progress and career progression). As a rule, biology departments had information about time to degree and percentage of matriculating students who obtained their PhD, but not about job placement. No biology department had a job placement adviser, although career counseling offices at some universities did try to help students leaving academic science find non-academic jobs.

By contrast, all of the professional schools – law, business, medical – tracked the salary and position of their graduates through Student Affairs or Career Services Offices. More often than not this information was advertised on school websites. The inaccessibility of specific information regarding pre-doctoral biosciences students enrolled in graduate programs over the last 10 years means that federal funding agencies regulating scientific development and growth are unequivocally flying blind.

Introducing career streams into academic research

Posted on June 4, 2012 by Jonathan Thon

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In the 1990s the typical PhD in biological sciences entered the job market in their mid 30s, after spending approximately 3.8 years as a postdoctoral fellow (National Academy of Science, Enhancing the Postdoctoral Experience for Scientists and Engineers). This is 3.6 years longer than it was in 1970 (National Research Council, Trends in the Early Careers of Life Scientists) and roughly 10 years shorter than what it is today.

It is not surprising then that so few PhDs continue into academic positions after receiving their graduate degree. A major failing of our graduate school system is that despite their program choices both Master’s and doctoral students are exclusively trained to become academic investigators. This is a problem when only 20 percent of doctoral students will ultimately become professors and the average age of independence in academic research is now in the mid-40s (A deeper look into the 80 percent of PhDs who do not become professors, and A new era of science funding – Part 4: Speaking up in support of federally funded research). Meanwhile, industries such as biotechnology, drug development, policy development, and scientific writing (amongst others) employ the remainder.

Indeed, a recent study by Fuhrmann et al. have found that at the University of California, San Francisco, nearly one-third of students midway through their graduate training intend to pursue a non-research career path (Improving graduate education to support a branching career pipeline: Recommendations based on a survey of doctoral students in the basic biomedical sciences. 2011. In other words, we are training our graduate students to excel at professions they will never hold. To support the growing number of research PhDs universities are graduating yearly for which faculty positions are not available, we have extended the duration of the postdoctoral research fellowship position. Originally intended to allow for furthering expertise in a specialist subject, acquiring new skills and methods, and developing one’s ability to run an independent research program by apprenticing under an established professor, this has become a repository of misallocated talent that delay a scientist’s entry into their first “real” jobs by more than five years (Careers for Postdoctoral Scientists: The Ever-Aging Postdoc).

For the majority of scientists that are forced to transition into other industries, the postdoctoral fellow stage represents a significant waste of time that does not adequately prepare them for the career they will ultimately elect – and yet, because of the enormous number of postdoctoral fellows feeding into these professions, it has become a prerequisite for most of these positions. As with any new profession, employment in an altogether different field carries with it its own learning curve, further delaying the career advancement of the scientist.

A significant departure from the current trend of expanding the supply of research scientists without evidence of imminent shortages in either the private or academic sectors is necessary (Supply Without Demand), and could be addressed by implementing career streams at the graduate and postdoctorate levels. While this is not a new idea (Elizabeth Marincola and Frank Solomon. The career structure in biomedical research: Implications for training and trainees, The American Society for Cell Biology on the State of the Profession. Molecular Biology of the Cell. 9:3003-3006. 1998), research institutions such as Harvard are increasingly deciding to go the other way, creating additional temporary, non-tenure-track Instructor and Research Associate positions that are in every way equivalent to a postdoctoral research fellow designation and meant to follow postdoctoral training.

In my next post I will tell you why this is a problem.

A call to arms

Posted on May 17, 2012 by Jonathan Thon

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Scientific research is a marathon, and if we fall behind now, while we are leaders in health innovation, the cost of recovering our position, in light of emerging economies with which we compete, will become progressively more expensive. Sustained increases in National Institutes of Health and Canadian Institutes of Health Research funding are critical to maintain North America’s innovation engines at a crucial time for research and the economy, and most importantly to improve the health and well-being of our populations.

Now is the time for scientists to advocate most strongly for national investment in biomedical research. Members of Parliament, Members of Provincial Parliament and Members of the Legislative Assembly in Canada, as well as senators and congresspersons in the United States are the decision-makers you elect to represent you – write to them. You can go to http://www.canada.gc.ca/directories-repertoires/direct-eng.html and enter your postal code (in Canada), orhttp://www.house.gov and enter your zip code (in the United States) to access your representative.

Things to remember when composing your letter:

  • Identify yourself as a constituent and a member of the scientific community
  • Ask that the legislator support sustainable funding priorities for your federal funding agency.
  • Briefly explain why these issues are important to you.
  • Acknowledge the efforts that are being made by their party
  • Give them your contact information and ask to be informed about the actions their office takes in response to your request.

Letters need to be kept simple and as personal as possible, with tangible examples of actions MPs, MPPs, and MLAs can take to change the landscape of how biomedical research is supported in Canada. These should be provided to the legislator in the form of a one-page cheat-sheet with your contact information included for reference. If dealing with your senator or congressperson in the United States you will need to ask to speak/meet with your representative’s health legislative assistant who handles health care issues in the district or state.

Giving opposition members speaking points against current government policies, emphasizing the economic relevance/importance of your position, and holding legislators accountable for providing examples of and justifying actions they have taken on their own promises are all good ways of having your opinions considered. After the meeting it is important to follow up with your representative within the week, whether or not the representative was supportive of your position. This is your chance to remind them of what you discussed and further emphasize the importance of their involvement on this issue.

Canada-specific:

  • Major research funding in Canada is done federally, but provinces are responsible for health spending and many provinces (e.g.: BC, Ontario, Quebec) have contributed to major infrastructure projects.

U.S.-specific:

  • States often put aside money for research into targeted areas (e.g. California’s support of stem cell research) and are generally more independent than Canadian provinces.
  • Many federal representatives will have specific assistants/aides for health related issues -ask to speak/meet with them

Example speaking points:

  • Low funding rates (NSERC PDFs, CIHR operating grants, etc.)
  • Low postdoctoral fellow salaries compared to other countries
  • Plus, 4 or 5 more good statistics that show why basic health research is a good investment or is currently underinvested.

While the argument for the government to prioritize an industry where the number of clinical advances, drug developments and cures is proportional to total research investment is not a difficult case to make – it needs to be made. I and others at The Black Hole continue to work at concentrating and contextualizing some of the more important issues facing early career scientists in Canada and abroad.

Take advantage of this resource and use hard numbers to emphasize your points. Addressing these concerns forces the issue to light, and commits politicians to publicly defensible positions for which they can subsequently be held accountable. Government agencies cannot lobby for themselves and policy makers do not share your unique perspective. Our health, economy, and the future of scientific progress are at stake, so step up and speak out.

Show me the money!

Posted on May 4, 2012 by Jonathan Thon

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It falls to scientists to speak up in support of federally funding research and in this third installment of a four-part series, I explore the economic cost of doing research in a cash-strapped system and the burden this is placing on young investigators.

To bring yourself up to speed, installements 1 and 2 are referenced below:

  1. Biomedical Research and Broken Clocks: All the Parts, but No Instructions
  2. A Difficult Pill To Swallow: The Harsh Realities of a 15% Funding Rate

As has been discussed here on and off for quite some time, 80% of PhDs in the US will not become professors. For the majority of these scientific investigators, the inability to secure a faculty position has meant that they must languish in a series of post-doctoral positions supported by grant-funded professors who are increasingly finding themselves with limited resources. The average age of independence in research is now in the mid-40s, a testament to the bleak prospects facing young scientists (PDF).

Given this highly unstable state of academic funding, it is not surprising that many investigators have chosen to transition into more secure professions like teaching, medicine or law. For an in-depth review of the career prospects of a post-doctoral research scientist please see Careers and Rewards in the Bio Sciences: The Disconnect Between Scientific Progress and Career Progression(PDF). The loss hurts our competitiveness in biomedical research and forces industry abroad.

Given our current economy, it is imperative that efforts to improve the nation’s fiscal stability be grounded in the long-term competitiveness of industries we currently head, and that we leverage our expertise in medical science and capacity to do high-tech research. This does not need to come from increased government spending alone. Whereas academic medicine cannot build R&D into the pricing of its services, universities profit directly from tuition fees, patents and personal endowments.

Since these revenues are derived from faculty teaching loads, the scientific success of their investigators, and established reputation of their research program, faculty support must be factored into departmental operating budgets, freeing up tax dollars to directly support research innovation. Another idea would be to create tax breaks for private donations to federal funding agencies in an effort to reduce their dependence on public dollars and incentivize industry investment in national research programs. In the United States (the same nation that passed the Bayh-Dole Act to spur commercialization of university research), government funding of university research exceeds business funding by an order of magnitude, and business investment in university research is nearly half that of Canada (PDF).

Finally, limiting the number of federal awards issued per investigator, most of which are held by senior faculty (PDF), would open up more funding opportunities to help support young investigators and significantly lower the age of independence. While the debate of whether to preferentially support established labs with proven track records over younger faculty with new ideas is ongoing, without early career support junior researchers will not succeed.

If we are unwilling to prioritize young faculty and share what wealth there is, perhaps the better question is “Should we continue training so many of them?”

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Risks of Hypoglycemia in Diabetics with Chronic Kidney Disease (CKD)

Reporter: Aviva Lev-Ari, PhD, RN

Risks of Hypoglycemia in Diabetics with CKD

By Mark Abrahams, MD

Reviewed by Loren Wissner Greene, MD, MA (Bioethics), Clinical Associate Professor of Medicine, NYU School of Medicine, New York, NY

Published: 03/13/2012

 http://www.medpagetoday.com/resource-center/diabetes/Risks-Hypoglycemia-Diabetics-CKD/a/31634

According to the National Institutes of Health (NIH), approximately 40% of adults with diabetes have some degree of chronic kidney disease (CKD).1 That’s a lot of patients—perhaps more than one might think.

What should we be doing differently for these patients? Sure, they should be getting an angiotensin-converting enzyme (ACE) inhibitor or an angiotensin receptor blocker (ARB) for renoprotection, and blood pressure and lipids should be aggressively managed, but how does (or should) our approach to managing their antidiabetic therapy change?

We might consider taking a more aggressive approach to their glycemic control. In clinical trials, tight glycemic control has been shown to be the primary determinant of decreased microvascular complications.1 However, once we’ve decided how aggressively to manage glycemia, the choice of which antidiabetic to use (and how to dose it) is especially important in these patients.

Unfortunately, when the therapeutic strategy is to maximize glycemic control, the risk of hypoglycemia also increases – in both frequency and severity.2 Patients taking oral antidiabetics that are primarily eliminated by the kidneys are particularly susceptible.1 Furthermore, it should be noted that older patients are also at higher risk.3

Dosing errors are common in CKD patients and can cause poor outcomes.3 Drugs cleared renally should be dose-adjusted based on creatinine clearance or estimated glomerular filtration rate (eGFR). Dose reductions, lengthening of the dosing interval, or both may be required.3

As metformin is nearly 100% renally excreted, it is contraindicated in a number of patients: when serum creatinine is higher than 1.5 mg/dL in men or 1.4 mg/dL in women, in patients older than 80 years, or in patients with chronic heart failure. The primary concern here is that other hypoxic conditions (e.g., acute myocardial infarction, severe infection, respiratory disease, liver disease) may increase the risk of lactic acidosis. Because of this danger, and despite the fact that metformin is usually the recommended first-line treatment for type 2 diabetes, one should use caution when considering metformin in patients with renal impairment.3

Similarly, sulfonylureas should be used with care in diabetics with CKD. The clearance of both sulfonylureas and their metabolites is highly dependent on kidney function. As such, severe and sustained episodes of hypoglycemia due to sulfonylurea use have been described in dialysis patients.2

Regardless of which antidiabetic agent is selected, HbA1c and kidney function should be regularly monitored and the antidiabetic regimen appropriately adjusted. As patients with type 2 diabetes tend to progress over time, most will require a combination of agents to achieve desired glycemic control. These combinations should be chosen carefully in patients with CKD.1

Finally, awareness of and screening for renal impairment in diabetics is a necessary precursor to successful intervention. In these patients, CKD is underdiagnosed and undertreated, and awareness of the disease is low among providers and patients alike.1

Early detection of disease via eGFR or urinary albumin excretion can lead to timely, evidence-based intervention and help prevent or delay progression of CKD. The benefit? Improved kidney and cardiovascular outcomes, and lower associated costs.1

References:

  1. Bakris GL. Recognition, Pathogenesis, and Treatment of Different Stages of Nephropathy in Patients With Type 2 Diabetes MellitusMayo Clin Proc. 2011;86:444-456.
  2. Cavanaugh KL. Diabetes Management Issues for Patients With Chronic Kidney DiseaseClin Diab. 2007;25:90-97.
  3. Munar MY, et al. Drug Dosing Adjustments in Patients With Chronic Kidney Disease. Am Fam Physician. 2007;75:1487-1496.

 

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Reporter: Aviva Lev-Ari, PhD, RN

July 20, 2012

The 2012 Intelligent Systems for Molecular Biology conference held this week in Long Beach, Calif., marked the 20th anniversary of what is considered the largest meeting in computational biology.

As part of the festivities at this year’s meeting, two founding members of the International Society for Computational Biology, which plans and manages ISMB, presented an anniversary keynote.

Lawrence Hunter, who directs the computational bioscience program and the center for computational pharmacology at the University of Colorado School of Medicine, and Richard Lathrop, a professor in the department of computer science at the University of California, Irvine, delivered the keynote, which traced the early days of the meeting, with its initial focus on artificial intelligence, to its current focus on computational biology.

BioInform caught up with Hunter, who was the first president of ISCB, after his talk to discuss the history of the conference and possible future directions for the community. What follows is an edited version of the conversation.

It’s been 20 years since the first ISMB. How has the meeting evolved over the years?

ISMB has gone through several stages. In the very beginning it was almost entirely computer scientists and there were really clear themes that emerged from the meeting. [For example, at] the third meeting … half of the papers were about hidden Markov models. As the field has grown and changed, there is a much less clear division between the computer scientist and the biologist. We’ve really become computational biologists and so the level of biological sophistication has gone up and the field has diversified so that there is really rarely a clear theme anymore; it’s multifaceted and diverse.

Another thing that’s changed is the orientation toward medicine. In the early days of the field, we were grappling with much more basic science problems and while there is still a lot of that, there is a much higher proportion of work that’s translational or clinical. Whether it’s drug repositioning, where I think there is real potential to change the pharmaceutical industry based on the kind of informatics work that’s done here, to an increase in the use of clinical data in the techniques that are being proposed here — whether it’s text mining or patient records or formalin-fixed, paraffin-embedded samples and the challenges in doing transcriptomics in those kinds of clinical samples — we are much more tightly connected to human health than we were 20 years ago.

Is that a good thing? Does the focus on health mean that bioinformatics tool development in other areas is being neglected?

I think it’s a good thing. Everybody wants to be relevant. Scientists don’t want to do things in the abstract; they want to do things that make a difference in people’s lives. One of the biggest ways to make a difference in people’s lives with bioinformatics is through medicine or pharmacology. There has never been a big contingent of folks working in agriculture but there are always a few … so far, the agricultural impacts have been smaller than the medical ones. And there are plenty of people doing basic science who are trying to understand how life works, [and] not so much trying to affect disease. I think there is a good balance and it will shift around from time to time. It would be great if there were more agricultural kinds of applications … [but] there is much more funding for things with medical applications than there are for ones with ag applications.

Following up on comments about funding, do you find that researchers have gotten better at including a budget for informatics in their grant proposals?

I think reviewers demand pretty sophisticated informatics in a lot of grants. For NIH grants, especially for the bigger, more prestigious ones — R01s or program projects or the [Clinical and Translational Science Awards] — all of those require a pretty good degree of informatics sophistication, I think, in order to do well. Looking over the last 20 years, one thing that has improved, although it could still use work, is study sections at [the National Institutes of Health], the review panels, becoming more sophisticated about computation. For a long time there was no standing study section at NIH that was specifically computational. Now there are two. There is also increasing sophistication on other study sections, so if you sit on an NIGMS panel, for example, there are going to be at least a couple of people who are pretty sophisticated about the informatics looking at those applications.

For the really large center proposals, and I am thinking now about the CTSA awards, there was such an emphasis on the informatics in the program announcement from the NIH that it changed institutions. Medical schools started adding divisions or departments of biomedical informatics in response to NIH requirements that the grant proposals be more sophisticated.

You mentioned earlier that ISMB has evolved since it first launched. Do you think that the meeting and ISCB in general have stayed true to their initial mandates?

It’s evolved. When we first put it together, we were thinking about artificial intelligence and robotics in molecular biology. It was much narrower. There were already conferences on, say, biological databases and we didn’t think that it was our topic. There was also the RECOMB [Conference on Research in Computational Molecular Biology] community, the algorithms community, and we separated from them too so that original vision was much narrower. ISMB has turned into a much more inclusive conference and ISCB a more inclusive society.

ISCB and ISMB both start with ‘IS’ but the ‘IS’es are different. ISMB, the conference, was about intelligent systems, that is, about AI. ISCB is the International Society for Computational Biology; it’s a much broader mandate. It includes databases and algorithms and visualization and all kinds of things that aren’t intelligent systems. That’s been a big change from the initial vision and, I think, ultimately a good one. I think the boundary lines were not productive and while I am still very interested in the artificial intelligence question, the blending of people working from different areas of computer science all sort of pulling towards solving problems motivated by biology has really been productive and so I am glad we’ve changed a bit from the initial vision.

Is there still room for AI?

The AI stuff has never gone away. There is tons of machine learning here, text mining, ontology, and knowledge representation here. One of the reasons I think this conference and this field and the original AI in molecular idea has been so successful is the technology works. It works in molecular biology almost better than it works in any other application area. So there is no shortage of intelligent systems at ISMB. It’s just more than that now.

Are there any computational issues that the community was dealing with 20 years ago that are still being dealt with today?

We go in cycles. If you go back to the very early ISMBs there was a lot of sequence analysis and alignment questions and relatively little dynamics. Fast forward 10 years, everything was microarrays and time series and concentration levels and sequence analysis was a boring solved problem. Fast forward 10 more years and we’ve gone back in a circle. Right now, microarrays are kind of a boring solved problem and sequence analysis is really interesting and hot again. The technology changes and so the problems change, nothing ever seems to stay solved. Either our ability to peer into the biology lets us know that we were naïve or over simplistic about something that we now need to go back and look at much more carefully. For example, the assumption that only protein-coding bits of the genome were transcribed underlay a lot of science for a long time. Now it turns out that a huge portion of the genome is transcribed and there is a lot of action going on in RNA editing and mircoRNAs and long non-coding RNAs are starting to look interesting again. As you look deeper, more interesting problems come up that you didn’t notice when you were making assumptions about how biology works.

It’s rare in our field that we prove some technique optimal. The best we can do is prove that my way of doing it is better than X,Y, and Z and so it’s a step forward but that always leaves the possibility that there is yet a still better way to do it and we still see people who are working on topics that have been well studied for a long time [such as] splice site identification, transcription start sites, structure prediction, function prediction problems that have been studied for a long time, yet new methods that are generally better come out. Even after working on it for 20 years, there is still the potential to do better.

Looking ahead 20 years from now, what do you see as the future of bioinformatics?

Let me take [a prediction] from my keynote. I think that we will see computer programs as increasingly independent and individuated intellectual partners. Right now, everybody using, say, Cufflinks uses the same version and it does the same thing every time. 20 years from now, I would expect that my computer program would be so customized to my way of thinking and what’s going on in my lab that the same computer program would do something different in somebody else’s lab. That doesn’t mean it’s not reproducible, we’ll know what it did and why, but that rather than having tens of thousands of copies that do the same thing, it’ll be more like having a computational member of the lab. It will know what we are after and what our interests are and what my collaborators want and who my competitors are and be much more individualized. I am not going to say that we’ll have a program that everyone thinks is a mind 20 years from now … but I think along the path to developing genuine artificial intelligence, all minds are unique, everybody is different, and that’s going to be increasingly true to programs too.

http://www.genomeweb.com//node/1108711?hq_e=el&hq_m=1314078&hq_l=7&hq_v=e1df6f3681

Uduak Grace Thomas is the editor of GenomeWeb’s BioInform. She covers bioinformatics, computational biology, and life science informatics. E-mail her here or follow her GenomeWeb Twitter account at @BioInformGW.

 

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Reporter: Aviva Lev-Ari, PhD, RN
July 25, 2012
Insights into protein folding may lead to better flu vaccine
folding proteins

S.B. Qian
This image shows shows mRNA (purple) with ribosomes (beige) bearing nascent protein chains (pink) in different stages of folding.

A new method for looking at how proteins fold inside mammal cells could one day lead to better flu vaccines, among other practical applications, say Cornell researchers.

The method, described online in the Proceedings of the National Academy of Sciences July 16, allows researchers to take snapshots of the cell’s protein-making machinery — called ribosomes — in various stages of protein production. The scientists then pieced together the snapshots to reconstruct how proteins fold during their synthesis.

Proteins are made up of long chains of amino acids called polypeptides, and folding gives each protein its characteristic structure, which determines its function. Though researchers have used synthetic and purified proteins to study protein folding, this study looks at proteins from their inception, providing a truer picture for how partially synthesized polypeptides can fold in cells.

Proteins fold so quickly — in microseconds — that it has been a longtime mystery just how polypeptide chains fold to create the protein’s structure.

“The speed is very fast, so it’s very hard to capture certain steps, but our approach can look at protein folding at the same time as it is being synthesized by the ribosomes,” said Shu-Bing Qian, assistant professor of nutritional sciences and the corresponding author on the paper. Yan Han, a postdoctoral associate in Qian’s lab, is the paper’s first author.

In a nutshell, messenger RNA (mRNA) carries the coding information for proteins from the DNA to ribosomes, which translate those codes into chains of amino acids that make up proteins. Previously, other researchers had developed a technique to localize the exact position of the ribosomes on the mRNA. Qian and colleagues further advanced this technique to selectively enrich only a certain portion of the protein-making machinery, basically taking snapshots of different stages of the protein synthesis process.

“Like a magnifier, we enrich a small pool from the bigger ocean and then paint a picture from early to late stages of the process,” Qian said.

In the paper, the researchers also describe applying this technique to better understanding a protein called hemagglutinin (HA), located on the surface of the influenza A virus; HA’s structure (folding) allows it to infect the cell.

Flu vaccines are based on antibodies that recognize such proteins as HA. But viruses have high mutation rates to escape antibody detection. Often, flu vaccines lose their effectiveness because surface proteins on the virus mutate. HA, for example, has the highest mutation rate of the flu virus’ surface proteins.

The researchers proved that their technique can identify how the folding process changes when HA mutates.

“If people know the folding picture of how a mutation changes, it will be helpful for designing a better vaccine,” Qian said.

“Folding is a very fundamental issue in biology,” Qian added. “It’s been a long-term mystery how the cell achieves this folding successfully, with such speed and with such a great success rate.”

Co-authors include researchers at the National Institute of Allergy and Infectious Diseases.

The research was funded by the National Institute of Allergy and Infectious Diseases Division of Intramural Research, National Institutes of Health Grant, Ellison Medical Foundation Grant and U.S. Department of Defense Exploration-Hypothesis Development Award.

 http://www.news.cornell.edu/stories/July12/ProteinFoldingQian.html

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Reporter: Aviva Lev-Ari, PhD, RN

NEW YORK (GenomeWeb News) – The Alzheimer’s Association and the Brin Wojcicki Foundation yesterday announced a partnership aimed at obtaining the whole-genome sequences of people with AD.

The Alzheimer’s Association and the Wojcicki Foundation are funding the project, which seeks to perform whole-genome sequencing on more than 800 people enrolled in the Alzheimer’s Disease Neuroimaging Initiative (ADNI), generating at least 165 terabytes of new genetic data.

Once the genomes are sequenced, the raw data will be made available to scientists worldwide to investigate new targets for risk assessment and new therapies and to gain new understanding into the disease, which afflicts an estimated 5.4 million Americans.

“The current ADNI database already includes detailed, long-term assessments of neuropsychological measures, standardized structural and functional imaging, and precise biomarker measures from blood and spinal fluid,” said Robert Green of Brigham and Women’s Hospital and Harvard Medical School, and who will coordinate the sequencing work within ADNI. “Adding whole-genome sequences to this rich repository will allow investigators all over the world to discover new associations between these disease features and rare genetic variants, offering new clues to diagnosis and treatment.”

The new project is an extension of ADNI, a public-private research project launched in 2004 with the goal of identifying biomarkers of AD in body fluids, structural changes in the brain, and measures of memory, in order to improve early diagnosis of the disease and develop better treatments. The National Institutes of Health leads ADNI and private sector support is provided through the Foundation for NIH.

ADNI is led by principal investigator Michael Weiner from the University of California, San Francisco and the San Francisco VA Medical Center. Green will collaborate with Arthur Toga of the University of California, Los Angeles, and Andrew Saykin of Indiana University on the sequencing work.

The genome sequencing will be done at Illumina.

http://www.genomeweb.com//node/1099936?hq_e=el&hq_m=1303351&hq_l=3&hq_v=e1df6f3681

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A slight mutation in the matched nucleotides c...

A slight mutation in the matched nucleotides can lead to chromosomal aberrations and unintentional genetic rearrangement. (Photo credit: Wikipedia)

Reporter: Venkat Karra, Ph.D.

A Global Approach to Global Genome Research: to address ELSI at Global Level..

via A Global Approach to Global Genome Research: to address ELSI at Global Level..

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Reporter: Prabodh Kandala, PhD

Screen Shot 2021-07-19 at 7.42.10 PM

Word Cloud By Danielle Smolyar

Scientists at The Scripps Research Institute have found the first chemical compounds that act to block an enzyme that has been linked to inflammatory conditions such as asthma and arthritis, as well as some inflammation-promoted cancers.

The new study, published recently by the journal ACS Chemical Biology, describes new compounds that inhibit an important enzyme called PRMT1 (protein arginine methyltransferase 1). The new inhibitors will be useful to scientists who study PRMT1-related biological pathways in cells and who are developing drug treatments for PRMT1-related inflammatory conditions and cancers.

Standard screening techniques had been unable to distinguish between compounds that inhibit PRMT1 and those that inhibit other common PRMT family enzymes. In the new study, scientists from several Scripps Research laboratories collaborated to devise the first PRMT1-specific screening technique. “We were able to target a screening probe to a specific amino acid found on PRMT1, but not on most other PRMT enzymes,” said the study’s principal investigator Scripps Research Assistant Professor Kerri A. Mowen.

Mowen has been studying PRMT1 since her graduate school days, and, like others in the field, has been acutely aware of the need for selective PRMT1 inhibitors. The enzyme modifies the functionality of proteins by attaching a methyl group to their arginine amino acids; as such, it is involved in some of the most basic processes in cells. For example, Mowen and her colleagues showed in 2004 that PRMT1 helps drive the production of the key immune-stimulating proteins interferon-gamma and interleukin-4.

But although PRMT1 was known to be responsible for nearly all the arginine methylation that goes in mammalian cells, no one had been able to develop selective PRMT1 inhibitors, since the 10 other PRMT enzymes are nearly identical, structurally and biochemically. Even the removal of PRMT1’s gene from lab mice as an alternative way to study its functions was problematic, since mouse embryos can’t survive without the protein.

Inspiration Close By

The inspiration for the new PRMT1-selective screening technique came from research performed in the neighboring laboratory of co-author Benjamin F. Cravatt III, who chairs the Scripps Research Department of Chemical Physiology. As reported in 2010 in the journal Nature, Cravatt and his team screened tens of thousands of human and mouse proteins for the presence of hyper-reactive cysteine amino acids, which almost certainly mark functional sites on those proteins. PRMT1 was found to be one of the reactive-cysteine-containing proteins — and all but one other, comparatively rare PRMT enzyme was known to lack that cysteine.

“We took that discovery a step further, and we were able to find a probe that specifically would recognize that cysteine in PRMT1,” said Mowen, who was one of Cravatt’s collaborators on the 2010 study.

She and her colleagues first verified that the reactive cysteine in PRMT1 is in the active site of the enzyme. They then found a fluorescent probe that would bind to that cysteine. If a test compound acted as an inhibitor by fastening to PRMT1’s active site, it should interfere with the probe’s binding, and the probe’s fluorescence-based signal therefore should be lower. By contrast, if a test compound failed to bind to PRMT1’s active site, the probe should bind normally and its signal should remain elevated.

“We were able to verify, using available non-specific inhibitors of PRMT enzymes, that they did indeed bind to PRMT1 and prevent the probe from binding, and that was the proof-of-concept that enabled us to go ahead with a screen,” said Myles B. C. Dillon, a graduate student in Mowen’s lab who was lead author of the study.

Exploring Libraries of Potential

Dillon and Mowen turned to collaborator Scripps Research Professor Hugh Rosen, curator of a library of 16,000 chemical compounds known as the Maybridge Hitfinder Collection. By applying these compounds, one by one, along with the probe molecule, to solutions of PRMT1, the team was able to determine the compounds’ abilities to bind PRMT1’s active site and thus act as inhibitors. Importantly, the setup was simple enough to be adapted, with Rosen’s help, as an automated, “high-throughput” technique, capable of screening thousands of compounds.

In this way, the scientists were able to sift through the compound library to find two candidate PRMT1-selective inhibitors. “They have good efficacy and specificity, and we might be able to modify them to make them even better,” said Dillon.

Mowen, Dillon, and their colleagues now have a National Institutes of Health (NIH) grant to use their screening technique with a 300,000-compound NIH library, also curated at Scripps Research. “Once we get the results from this larger screen, we’ll consider our best inhibitor compounds and decide which ones to start optimizing,” said Dillon.

To Mowen, the success of the project owes much to the collaborative spirit at Scripps Research. “Many labs here are developing cutting-edge technologies that empower other labs’ work, and certainly we were able to benefit from that,” she said. “It’s a very supportive, synergistic environment.”

http://www.sciencedaily.com/releases/2012/05/120511104815.htm

Journal reference: Myles B. C. Dillon, Daniel A. Bachovchin, Steven J. Brown, M. G. Finn, Hugh Rosen, Benjamin F. Cravatt, Kerri A. Mowen. Novel Inhibitors for PRMT1 Discovered by High-Throughput Screening Using Activity-Based Fluorescence PolarizationACS Chemical Biology, 2012; : 120420132930009 DOI: 10.1021/cb300024c

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