Wednesday, March 21, 2007

Give Us More Money, or Else!

Be Very Afraid!

The March 19, 2007, press release from Johns Hopkins University begins like this:

JOHNS HOPKINS JOINS SEVEN OTHER INSTITUTIONS TO WARN CONGRESS ABOUT DANGERS OF FLAT FUNDING OF BIOMEDICAL RESEARCH
New Report Outlines Threat to Medical Progress in Combating Cancer, Alzheimer’s Disease, Spinal Cord Injuries and Other Conditions

Johns Hopkins University and a consortium of seven other leading U.S. scientific and medical institutions today warned Congress that persistent flat funding of biomedical research could thwart advances in treatments for such diseases as cancer and Alzheimer’s disease, and erode U.S. dominance in science.

In its 21-page report, Within Our Grasp-Or Slipping Away? Assuring a New Era of Scientific and Medical Progress, the consortium said years of stagnant budgets for the National Institutes of Health (NIH) also has interrupted promising research and forced young investigators to leave their scientific careers.

The group calls on Congress to provide more consistent and robust NIH funding levels to maintain U.S. global leadership in biomedical research. Other members of the consortium include the University of California system, Columbia University, Harvard University, University of Texas at Austin, Washington University in St. Louis, the University of Wisconsin Madison, and Yale University....
This is hoodwinking and fear-mongering at its best, er, lowest.

Rather than torture readers by picking the report apart one sentence at a time, I'll debunk it globally and then will look at the featured quotes, since the authors felt these gems to be particularly convincing.

Global debunking

The spin supporting the report has been significant. One of the "contributers" to the report is Joan Brugge, chair of the department of cell biology at Harvard Medical School. She is quoted in a United Press International story as warning us that the fight against cancer could lose ground if ever-increasing amounts of tax money aren't provided to scientists. It's like we're being held hostage. Maybe we'll all start smoking again as we worry about these scientists struggling to make the mortgage payments on their summer homes.

Brugge says: "The number of drugs moving into the pipeline based on our new, more profound genetic and molecular understanding of cancer are extraordinary -- and there's no money to handle the testing of these compounds."

Let's think about this pipeline for a minute.

At one end (think of this as the gaping maw of the universities screaming "More, more, more! Feed me Seymore!") we are pouring in literally tens of billions of dollars for basic research on species other than humans, and between 1998 and 2003, the amount more than doubled. At the other end -- if this research paradigm is legitimate -- we would expect a somewhat proportional increase in benefit. But the results have been very unimpresive.

Consider Dr. John P. A. Ioannidis's 2004 commentary in the Journal of Translational Medicine regarding the pipeline that begins: "There is considerable evidence that the translation rate of major basic science promises to clinical applications has been inefficient and disappointing."

Consider Dr. Roger Rosenberg's editorial comments in the Journal of the American Medical Association regarding the pipeline:
Lives are literally being lost daily because of inertia in the system to move promising research quickly enough to the patient in need... There is an assumption that the recent exponential growth of scientific information about disease, as evidenced by the substantial increase in the numbers of published articles in biomedical journals, heralds a rapid move to improve human health.

This illusion is the subject of an intense analysis.... [Rosenberg, RN. Translating Biomedical Research to the Bedside: A National Crisis and a Call to Action. Journal of the American Medical Association 2003;289:1305-6.]
In 2004, William Richard Rodriguez, M.D. Chief Medical Director, Veritas Medicine and Instructor in Medicine, Harvard Medical School had this to say:
Exactly one year ago, the nation's most thoughtful and deliberative body devoted to translating the fruits of biomedical research into meaningful improvements in patients' lives … released a quiet, highly critical indictment of the biomedical research effort in the United States.[Rodriguez, WR Can biomedical research in the United States be saved from collapse? 2004 MebMD, Veritas Medicine.]
Rodriguez said that enormous sums of money invested in biomedical research is being wasted because of "inertia and disorganization" because of two stumbling blocks: "difficulty in translating laboratory findings into results that actually make a difference to patients; and difficulty in taking proven, successful treatments out of the research setting where only a few patients can use them, and into the real world."

In otherwords, dumping massive amounts of money into the gaping maws of the universities has made little difference to patients. And now, they want even more.

You can tout the possible benefits of drugs and treatments in the pipeline all you want, but if nothing's coming out, pouring in good money after bad is just dumb.

Notice too, the first stumbling block: "difficulty in translating laboratory findings into results that actually make a difference to patients." This refers to the near impossibility of translating animal data into human data.

Those gems

Sprinkled throughout the report are statements by the "contributers" that seek to convince Congress with nothing more than blatant appeals to authority and fear mongering; but then, they've nothing else to draw upon. Let's look at some of these gems:

Before the human genome was sequenced, researchers would take a single protein and study it intensely. It was like studying a single screw from an airplane to figure out how the airplane flies. With the genome sequence and new tools, we now have the complete parts list and can begin to understand the collective behavior of the components. There’s no way we could've done that previously.
Vamsi Mootha, M.D.
Massachusetts General Hospital and Harvard Medical School
In otherwords, in the very recent past he and others were making wild and silly claims about the importance of their research and its liklihood to lead to benefit. But now, it's important.

Here's a quote from one of Mr. Mootha's recent papers: "[W]e have mapped 1,404 proteins to ten subcellular locations in mouse liver..." Whoo-hoo!

The biomedical research effort in the United States has far exceeded that in any other country—largely due to the steady funding of the NIH research grant program. But we are beginning to lose our competitive edge because of the funding crisis at the NIH. Once the impetus is lost, I fear it will be difficult to reverse.
M. Daniel Lane, Ph.D.
The Johns Hopkins University School of Medicine
The United States spends vastly more on biomedical research than the rest of the world. According to the World Health Organization, the U.S. spends a higher percentage of its gross domestic product on health care than any other country but ranks 37th out of 191 countries according to its performance. According to a 2006 report from Save the Children (see CNN), the United States has the second worst newborn mortality rate in the developed world, and American babies are three times more likely to die in their first month as children born in Japan, and newborn mortality is 2.5 times higher in the United States than in Finland, Iceland or Norway.

Who gives a hoot about "our competitive edge" if American babies, pregnant mothers, or anyone else, aren't getting the healthcare they need?

Here's a quote from one of Mr. Lane's recent papers: "Fatty acid synthase (FAS) inhibitors, administered systemically or intracerebroventricularly to lean or obese mice, increase hypothalamic malonyl-CoA leading to the suppression of food intake." Whoo-hoo!
I do science because I believe I can better the lives of patients.... Have you seen the bellies of patients who inject themselves with insulin? Or the skin of women with multiple sclerosis? They have so much scar tissue that each new injection is terribly painful. We owe it to our patients to come up with solutions.
Nicholas Peppas, Sc.D.
The University of Texas at Austin
Here's a quote from one of Mr. Peppas' recent papers: "The objective of this study was to elucidate the mechanisms contributing to oral bioavailability of insulin by poly(methacrylic acid grafted with poly(ethylene glycol)) (P(MAA-g-EG)) hydrogels using the gastric and intestinal fluids from rats."

Mr. Peppas might be genuine in his concern for human patients, but the potential income from his nineteen patents might also be a factor. Which makes me ask, why should taxpayers be forced to help promote his business interests?

And, though I pretend no expertise, maybe Mr. Pappas' description of an "insulin belly" is intended to provoke more concern than is due. I found this on the Humalog website: "[Y]ou may be new to giving yourself an injection. The first question many people in your situation ask is, 'Will it hurt?' Today, insulin needles are short and tiny, so there is minimal discomfort." And, there is an accompanying graphic pointing out the many locations available for an injection. But maybe Humalog is lying.
The doubling brought in a cohort of research ‘baby boomers.’ These new investigators suddenly have to compete heavily against each other and against senior investigators for grants. Many of them are leaving. This is a crisis for the research community. What is going to happen to the future of health research in the U.S?”
Lee Riley, M.D.
University of California, Berkeley
It's a crisis! Right. Ten years ago the research community told the public and Congress that if only they had more money they'd be sure find a cure for Cancer, Alzheimer’s Disease, and Spinal Cord Injuries, and you name it. Now, after more than doubling the budget for basic research, they are telling us its a crisis. What gives?
The inherent risk taking—the driving engine for research—that’s the heavier toll of flat funding. People don’t take as many risks. You can’t afford to swing the bat and miss too many times.”
Jerry Chi-Ping Yin, Ph.D.
University of Wisconsin-Madison
Hum, Mr. Yin seems to have done quite well for himself inspite of discoveries like this: "Using a model of protracted social isolation in adult rats, we observed increased anxiety-like behavior and deficits in both the latency to initiate sexual behavior and the latency to ejaculate."
In the past, it took four to five years of work to characterize genes involved in one species, then jump to humans or mice to ask its role in disease. Now we can do that in 10 minutes.”
Carol Greider, Ph.D.
The Johns Hopkins University School of Medicine
10 minutes? Ten years ago she wrote:
We are interested in using the mouse as a model system for the study of telomerase. We studied telomerase activity and expression of the mouse telomerase RNA component (mTR) in two different transgenic mouse models of multistage tumorigenesis: models of islet cell carcinoma and squamous cell carcinoma.
Today, she says on her website:
To understand how telomere functions to provide chromosome stability and how telomerase might play a role in cancer, we generated a telomerase null mouse. Mice that lack the gene encoding the mouse Telomerase RNA (mTR) show progressive telomere shorting during successive breeding. The mice are viable for up to six generations although in the later generations there is severe reduction in fertility due to apoptosis in the germ cells. Crosses of these telomerase null mice to other tumor prone mouse models suggest that under some circumstances tumor formation can be greatly reduced when telomerase is absent.
She just wants more money.
Microchip technology allows us to scan for SNPs—single changes in the human genome. Originally, one chip could scan DNA for several hundred SNPs. The next generation chip will cover 1 million SNPs. We are using this technology to scan DNA from 1,000 families with Alzheimer’s, looking for common genetic patterns and the genes involved in late-onset Alzheimer’s disease.”
Leon Thal, M.D.
University of California, San Diego
Mr. Thal seemed to be claiming that without ever increasing amounts of money, researchers like him would what? Stop using gene chips? Here's how his website starts out:
My current research interests focus on three areas: the effects of basal forebrain lesion-induced memory loss, clinical pathological correlations in Alzheimer's disease (AD), and the conduct of clinical drug trials in AD.

In the laboratory, we are studying destruction of the basal forebrain in the rat which results in a marked decrease in cortical cholinergic markers as well as a multiplicity of learning and behavioral deficits secondary to impaired attention and acquisition.
As far as I know, people with Alzheimer's disease usually develop the symptoms in the absence of destruction of the basal forebrain. But what do I know?
Whatever you do to understand how a bacteria causes a disease, helps to understand how to prevent it.
Jorge Galán, D.V.M., Ph.D.
Yale University School of Medicine
I hope he meant to say that learning how a bacteria causes a disease might help one find a way to prevent it. The idea that whatever one does will be of value is just dumb. But, maybe this attitude -- anything a researcher chooses to do is meritorious -- contributes to the failure of basic research to deliver on its promises. And, maybe that explains why he thinks this sort of research is worthy of more money:
[W]e show here that mice deficient in the adaptor protein myeloid differentiation factor 88 (MyD88), which is required for signaling through most toll-like receptors, can be stably colonized by C. jejuni but not by isogenic derivatives carrying mutations in known virulence genes.
Have you noticed the trend in the research being conducted by the report's "contributers" yet?
We have learned so much about how diabetes and obesity damage blood vessels. All of the consequences of diabetes—kidney failure, blindness, loss of limbs, heart disease, and stroke—are vascular issues. And, in obesity, fat cells are factories of inflammatory substances that harm the blood vessel walls. All this knowledge comes from basic research.
Amparo Villablanca, M.D.
University of California, Davis
"Basic research" is code for experimentation on animals. Ms. Villablanca is a true believer; she probably believes that air travel is the result of animal experimentation as well. One of her recent papers starts out like this: "The overall goal of this project was to examine the interactions of hyperglycemia and loss of ovarian hormones on the artery wall in a type I diabetic mouse model."
Our product is not just our technology or medical breakthroughs. Our College of Natural Sciences alone puts 1,000 undergrads in research situations in labs, and most with NIH funding. That is a catalyst for creating innovative new scientists.”
Brent Iverson, Ph.D.
The University of Texas at Austin
Here's what Mr. Iversen has to say about his recent research: "These results represent the detection of free PA and LF by ELISA in the systemic circulation of two animal models [guinea pigs and rabbits] exposed to either of the two fully virulent strains of anthrax." Whoo-hoo!
Ten years ago, the search for treatment for spinal cord injury was a daunting and hopeless task. Then molecules like NOGO were discovered. Now there is hope. The neurological sciences are on the launching pad of a revolution.
Stephen Strittmatter, M.D., Ph.D.
Yale University School of Medicine
It's always, "We're on the launching pad," or "A breakthrough is just around the corner!" A recent Strittmatter discovery: "Corticospinal axons extend within the lesion site, but not caudal to it, after dorsal hemisection in the transgenic mice." Bet you didn't know that!
Studies now show you can train spinal cord circuits to restore function. Understanding the basic circuitry of the spinal cord has the potential to address a wide variety of human diseases—from Lou Gehrig’s Disease, to spinal muscular atrophy in children.
Thomas Jessell, Ph.D.
Columbia University
Only a cad wouldn't want to give endless and vast sums of money to help children with spinal muscular atrophy. Do you think Jessell's research involves children with spinal problems? Nope, almost all of his work is focussed on chick embryos. The rest uses mice and mouse cells.
Until recently, young minority investigators have been making unprecedented gains in the laboratory and in access to career-making grants. Their work is addressing everything from the biology of cardiovascular disease to cancer, and their research is generating knowledge and applying it in ways that will help eliminate health care disparities between minority groups and the larger population.

A flattening of the NIH budget—in real terms, a decrease in funding is already having a serious impact on the ability of these young investigators to realize sustained federal support. Without reasonable growth in NIH funding of basic science, our nation will be at risk of losing the remarkable perspective this generation of researchers brings to science.
David Nichols, M.D.
Vice Dean for Education
The Johns Hopkins University School of Medicine
That makes sense. If there isn't money to burn, the major research universities dump the minorities. If we don't give the NIH ever increasing sums, we hate children and minorities.
Young people are not going to pursue a career in science because the funding situation is so bleak. That will have a generational impact that will take
15 years to fix.
Richard Davidson, Ph.D.
University of Wisconsin-Madison
Complete crap from a scientist who is content to allow decades of his research data be destroyed rather than risk the public seeing what he does to monkeys in his lab. What a guy!
We have led the world in biomedical sciences—primarily due to NIH support. We’ve created an infrastructure that draws the best people in the world. We’ve spawned a biotech industry second to none and a pipeline of products. The fuel has been NIH funding. Choking that off is shortsighted and will have economic impacts.
Samuel Stanley, M.D.
Washington University in St. Louis
Well, there could be some economic impact if we really took the time to fund important and meaningful research instead of the deadend studies represented by the "contributers" to this report. The main impact will be the unemployment premiums we will have to pay until these bums can find gainful employment. Mr. Stanley uses severe combined immunodeficient (SCID) mice. He has explained that a decade of research using animals as models of amoebic infections in humans has led to no human trials.
Over the past decade, progress in vaccine development has been facilitated by new animal models that allow better testing of potential vaccine candidates and the application of recombinant technology to vaccine design. Oral vaccines and DNA-based vaccines have been successfully tested in animals models for immunogenicity and efficacy. There has been significant progress on a number of fronts, but there are unanswered questions regarding the effectiveness of immune responses in preventing disease in man and, as yet, no testing of any of these vaccines in humans has been performed.
He even admits that improved sanitation could eradicate of the disease.
Very, very productive scientists are doing no research. They are spending all of their time trying to get their labs funded again.
Robert Siliciano, M.D., Ph.D.
The Johns Hopkins University School of Medicine
This must explain where the public's money is actually going. Presumably, when Mr. Siliciano gets a grant, he pays himself to write more grant proposals and appeals to Congress like this one. Who paid for this report? Did the "contributers" record their own time and refund that percentage of their federal grants? This must be what Mr. Siliciano means by being productive:
There is currently no SIV macaque model in which the effects of combination antiretroviral therapy on tissue immune responses and latent reservoirs have been measured. This study was performed to define the impact of combination therapy on the specificity and distribution of the T lymphocyte response in multiple tissue compartments. Pigtailed macaques (Macaca nemestrina) were infected with SIV/17E-Fr...
Studies of different diseases in differents species are unlikely to ever be very productive if productivity is measured by how much the results help humans. So far, the SIV studies have been a colossal failure.
The last 10 years saw a tremendous build up in scientific capacity. The country needs this. The scientific community drives the economy. In biology, it drives the pharmaceutical industry, and will help people live longer in a productive way. Now, the rug has been pulled out. We’ll lose manpower to European countries, India, China, and Japan.”
Eric Kandel, M.D.
Nobel Laureate, Columbia University
Spare me the drama. Mr. Kandel's Nobel does not seem to have dampened his ego or his xenophobia. Here's the title and a link to one of his recent papers: Identification of a Signaling Network in Lateral Nucleus of Amygdala Important for Inhibiting Memory Specifically Related to Learned Fear. I hope he loses all his funding.
The impact of flat funding has been felt all over. Certainly, senior investigators are not immune. It is causing us to reduce the size of our labs. People are working on conservative topics. And there will be less international collaboration in the future, because people are feeling less inclined to split resources.”
Jon Clardy, Ph.D.
Harvard Medical School
Flat funding? Consider "contributer" Richard Davidson's funding over time.
The doubling built the momentum. Then the momentum comes crashing to a halt. That threatens the foundation in a very insidious fashion.”
Ira Mellman, Ph.D.
Yale University School of Medicine
Mr. Mellman's momentum: "In vivo, Myo1f-deficient mice showed increased susceptibility to infection by Listeria monocytogenes and an impaired neutrophil response. Thus, Myo1f directs immune cell motility and innate host defense against infection."

This report, Within Our Grasp-Or Slipping Away? Assuring a New Era of Scientific and Medical Progress, is a perfect example of the hoodwinking that keeps the vivisection industry afloat. Throughout the report the authors employ sick children, cancer, Alzheimer's, anything that might evoke our fear or evoke our fundamental concern for others in a seedy attempt to grub more money for deadend archaic experimentation with animals.

Looking deeper at that researchers' actual work, it is clear that they are part of the obstruction in the biomedial pipeline. The real constipation in the system comes from clinical scientists and epidemiologists having to having to compete with vivisectors for funding.

Throughout this essay, I've repeatedly put quotation marks around the word contributer. The researchers cameoed here, probably contributed to the report to the degree that they contribute to progress in medical care. It's all smoke and mirrors.

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