BioScience Biz

SBIR (non)Authorization Redux?

The latest word from Washington is that getting the SBIR reauthorization passed before it expires on March 20 is about as unlikely as the Cubs winning the World Series without a shortstop.  In order to keep the program alive until Congress can get around to the reauthorization, a continuing resolution (CR) is needed to temporarily extend its life. In fact, the SBIR program currently lives on via CR life-support since the last Congress did not complete the reauthorization bill.

The SBIR Program, created by the Small Business Innovation Development Act of 1982, periodically comes up for reauthorization every few years.  It was reauthorized in 1986, 1992, and 2000 and was slated again for September 2008; but, instead, congress failed to act and the program was temporarily extended by CR to March 20, 2009.

"You are encouraged to contact your congressional representatives..."

In 2008, Nancy Pelosi’s (D-CA) House made a heavy-handed attempt at the reauthorization, and under pressure from the biotech lobby, a bill (H.R.5819) was strong-armed through the House Small Business Committee. A major point of contention was whether to allow companies that are majority-owned by VCs to be eligible for SBIR funding—currently they are not. In other words, the debate centered on whether to emphasize the “S” vs the “B” in the reauthorization act.  To the consternation of the small business community, which was not allowed any input by the Committee, the bill passed and SBIR eligibility was extended to companies mostly owned by VCs.

Over on Harry Reid’s (D-NV) side of the Capitol, and under the leadership of Senators John Kerry (D-MA) and Olympia Snowe (R-ME), the Senate Small Business and Entrepreneurship Committee recommended a compromise bill (S.3362) that was supported by both the biotech and the small business lobbies.  Despite this broad and bipartisan support, Reid never scheduled a vote on it and the 110th Congress adjourned without completing the SBIR reauthorization.

Both bills are now moribund and the SBIR program is on its last legs unless another CR is passed.  The 111th Congress will have to start from the beginning on a new reauthorization bill, but efforts to reconsider the reauthorization bill have not yet begun.  Even if Congress began work on the bill today, it is unlikely that it would make it to Obama’s desk before the end of this year, several months after the program is scheduled to expire. Hence, another CR is urgently needed in order to avoid interruption in the SBIR program.

You are encouraged to contact your congressional representatives to urge them to take action to ensure that the SBIR program does not die from neglect.  Here is a template of a letter you can send to your Representative and Senators. And If you are worried about that SBIR grant application you plan to soon submit, you might consider sending a letter to those who held up the reauthorization last year, including every member of the House Small Business Committee as well as to Senate Majority Leader Reid.

Tell them what an important “stimulus” the SBIR program is for business development, job creation and the economy.  That ought to get their attention.

Induced pluripotent stem cells steal the limelight from embryonic stem cells, by Steven S. Clark

Recent stem cell headlines are all about how adult cells can be reprogrammed into induced pluripotent stem cells (iPS), which was recently hailed as the biggest scientific breakthrough of 2008.  All of this attention to iPS cells and hardly a word about embryonic stem cells (ESCs)—have ESCs lost their luster since scientists figured out how to reprogram adult cells back to the primordial stem cell state?

In reality, iPS cells have been around longer than ES cells.  In cloning the sheep Dolly in 1996, Scottish scientist Ian Wilmut took a single adult cell and injected its nucleus into a sheep egg from which the nucleus had been removed.  The cellular environment of the egg reprogrammed the nucleus of the adult cell so that it was able to give rise to Dolly. 

Last year, the laboratories Jamie Thomson at the University of Wisconsin-Madison and of Shinya Yamanaka, from Kyoto University, reported that this reprogramming could be done by simply expressing only three or four genes in an adult cell.  More recently reprogramming has been used by Harvard professor, Kevin Eggan, to derive iPS cells from patients with ALS (Lou Gehrig’s disease) and by UW-Madison professor, Clive Svendson, to derive iPS cells from patients with another neurodegenerative disease, spinal muscular atrophy (SMA).  Both iPS cell lines were then used to grow the defective neurons in the lab giving the scientists their first access to the very cells that caused the respective neurodegenerative diseases.  This creates a powerful research tool that will enable researchers to study the disease process and find ways to halt it. 

“Clinical trials” using iPS cells

The benefits of iPS cells don’t stop there.  Madison, Wisconsin-based Cellular Dynamics International (CDI) recently produced one of the world’s first commercial stem cell products, ESC-derived cardiomyocytes.  These are functional heart cells that CDI produces and sells to pharma companies for drug and toxicity testing.  But CDI also has a robust research effort to efficiently produce iPS cells, possibly without having to introduce exogenous genes into the adult cells.

“We have a large scale research activity to create a vector-free methodology for no integrated DNA (in the iPS cells),” said Chris Kendrick-Parker, Chief Commercial Officer at CDI.  The company is now filing patents and Kendrick-Parker was not at liberty to say if CDI has developed a DNA-free method for inducing iPS cells.  However, he did say that the company is “looking at all options.”

Kendrick-Parker believes that CDI will soon switch exclusively to using iPS cells to develop heart and other cell types for sale to pharma and researchers.  The advantage of iPS cells he said is that they can be used to produce adult tissues from people representing different ages, ethnic types and sexes as a way to model the human heterogeneity in tissue culture.  This way, “drug companies can actually recapitulate (in tissue culture) what happens in clinical trials,” Kendrick-Parker said.   

For this to happen, Kendrick-Parker says that CDI and other companies will use iPS technology to make a library of iPS cells from a wide range of people in order to reflect the genetic heterogeneity of the population.

Most investigational or even post-market drugs fail due to liver or cardiotoxicity in a subset of people, which is “why pharma is so interested in these (iPS-derived) models,” said Kendrick-Parker.  The cells should allow drug makers to identify organ-specific toxicities before clinical trials begin, thereby saving much time and money bringing a new drug to market, only to have it fail.  For example, having iPS-derived cardiomyocytes from a large patient population might have identified, early on, the cardiotoxicity of Vioxx, saving Merck & Company a great deal of money getting the drug to market and in subsequent litigation fees.

iPS cells in the clinic?

But what about using iPS cells to directly treat disease?  After all, they have been widely touted as the great ethical hope for stem cell therapy since they don’t involve destroying human embryos. 

Currently, iPS cells are made by expressing a few genes in an adult cell, which turns back the cells' developmental clock to an embryonic-like state from which they can become any of the body's 220 different cell types. Yet, the genes used to reprogram adult cells are, themselves, associated with cancer, so iPS cells made this way will not be used clinically.

However, last November, Thomson opined that in about six months, it will be possible to make iPS cells without having to resort to oncogenic gene expression.  While this will eliminate the immediate problem to using the cells clinically, they still face significant hurdles before being used to treat specific diseases.  In fact, Thomson also suggested that there may be problems with iPS cells, saying that there are “dark clouds on the horizon”.

Eric Forsberg, Director of the WiCell Research Institute, explained that reprogramming of adult cells is extremely inefficient, meaning that for some reason, it is only the rare adult cell that can be successfully re-programmed.  This suggests that other unknown factors affect the ability of each cells’ genome to be reset to an embryonic state. 

Researchers also know that reprogramming is incomplete.  The genome clock is not completely reset and this Incomplete reprogramming likely plays a role in the health problems that cloned animals have—Dolly had arthritis and was euthanized due to progressive lung disease.  This raises the possibility that tissues developed from reprogrammed iPS cells might not function normally.

Forsberg pointed out that the extent to which a person’s genome is reset can vary from person to person and this could mean that each person will require an individualized reprogramming regimen in order to create iPS cells for therapeutic use.  But, it is unlikely that the FDA would approve such an individualized protocol—they like uniformity and conformity in therapeutic protocols, not different protocols for different people

Thus, while iPS cells provide enormous potential for learning how human disease develops and progresses and for cost-effective development of new and safer drugs, they are still a long ways from the clinic.  In fact, ESCs will likely find clinical use before iPS cells do.

Embryonic stem cells after a decade of hope…or was it hype? By Steven S. Clark

As we reach the ten year anniversary of UW-Madison Professor, Jamie Thomson’s, discovery of how to grow human embryonic stem cells (ESCs), one wonders whether this has been worth the controversy that ensued over the destruction of human embryos in order to obtain the stem cells.  After all, no therapies have come from the discovery, so were opponents correct that this research was not only unethical, but also irrelevant?

While there have been no headline-grabbing ESC-based therapies, the technology is surely changing the way that medicine will be done.  This was illustrated by recent events in Madison, including the World Stem Cell Summit held last September and a more recent celebration of the ten-year anniversary of Thomson’s discovery, put on by the Wisconsin Academy of Arts and Sciences.  The Anniversary event featured keynote talks by Thomson and Michael West, CEO of BioTime, Inc., and founder of Geron, a West Coast stem cell company.

Thomson sounded his usual cautionary note, saying that it will be very difficult to use ESCs to directly treat disease.  But, he also said that even if they never make it into the clinic; ESCs will profoundly affect the future of medicine.  ESCs give us laboratory access to human tissues that we had not been able to get at before.  This lets scientists see what goes wrong with the specific cell types that cause Parkinson’s and cardiovascular diseases, diabetes and other maladies.  This, Thomson said, will lead to the development of new drugs and therapies to treat and prevent such diseases.  

Thomson also explained that the different cell types that can be derived from ESCs enables researchers to directly test new drugs on different human tissues.  He suggested that this will both dramatically reduce the number of animals used in drug and toxicity testing and allow more precise assessment of new drug efficacy and toxicity.  

This was put into perspective at the Stem Cell Summit, by John McNeish, head of Pfizer’s Regenerative Medicine efforts. He said that 10-16% of all new drugs fail during Phase I clinical trials alone due to cardiotoxicity.  Many more drugs fail due to liver, kidney and other organ-specific toxicities.  Overall, about 92% of new drugs that enter clinical trials fail due to lack of efficacy or to toxicity, according to the FDA’s web site. This means that potential drug toxicity is inefficiently measured in current animal models, making drug makers gamble early on that their new drugs won’t show organ-specific toxicity—a gamble that they lose nine times out of ten.  ESC technology, therefore, promises to provide tissues on which to test and eliminate potentially toxic drugs much earlier in the development pipeline, potentially saving billions in drug development costs, according to the FDA.  

ESC-derived research tools are entering the marketplace

Thomson and others from the UW-Madison, recently founded Cellular Dynamics International, or CDI, to grow different tissues from ESCs.  According to Tim Kamp, a UW-Madison cardiologist and CDI co-founder, the company now sells heart cells to Roche and Covance for drug testing purposes.  CDI grows the heart cells in-house and then sells them as research tools. Thus, they retain control of the ESCs and the developmental process, while providing a renewable stream of cellular tools that researchers can purchase.  At this time, CDI only markets heart cells, said Kamp.  But, according to Chris Kendrick-Parker, CDI Chief Commercial Officer, the company has agreements with, or is talking to the “all of the top 20 pharma companies” to provide cells for toxicity testing.

Besides CDI, the Menlo Park biotech company, Geron Corp., and San Francisco’s Vistagen Therapeutics also use ESCs to produce cells from the heart, pancreas, liver and other organs for similar purposes.  The European company, Cellartis provides AstraZeneca with ESC-derived liver cells for toxicity testing, but only at very low numbers that are not useful for high-throughput-screening of new drugs.  Cellartis also provides Pfizer with embryonic cells to test for birth defects.  Clearly, ESCs as drug testing and research tools is a growing international market, which Pfizer stem cell expert, John Hambor, said at the Stem Cell Summit, currently stands at $1.5 billion and is predicted to grow 20% annually in the foreseeable future.

Clinical trials on the horizon?

Michael West is more optimistic than Thomson that ESC-based therapies will soon happen.  He cited the very high interest in the technology shown by several biotech and pharmaceutical companies as the driving force that soon will propel ESCs into the clinic.  

Some biotechs already are pushing hard to begin clinical trials of ESC-based therapies. For instance, last Spring, Geron submitted an Investigational New Drug application (IND) to the FDA for permission to undertake the first ESC clinical trial to treat spinal cord injuries.  According to a company press release, the trial had been in the works for four years, but the FDA issued a Clinical Hold because they have not yet established ensure safety and efficacy guidelines for ESC-based therapies.  According to an article last May in the science journal, Nature, there also is speculation that President Bush’s objection to ESC research helped force the FDA to put the trial on hold.

Geron also is planning ESC clinical trials for heart disease, while Advanced Cell Technology in Los Angeles has indicated that it is close to submitting an IND to use ESCs to treat macular degeneration.  San Diego’s Novocell, with funding from Johnson & Johnson, is preparing for ESC clinical trials to treat diabetes.

So, ten years after Thomson’s discovery, ESCs are just now entering the market as research tools for drug and toxicity testing and clinical trials loom on the horizon.  At this point, the holdup is so the FDA can figure out how to monitor the trials.  Furthermore, with the Obama administration, political constraints on the FDA to approve ESC-based trials will likely be removed next year. 

Pharma makes a pragmatic left turn in this election, by Steven S. Clark

Reversing trends where drug makers routinely throw their financial support behind the Republicans, big pharma decisively backed the Democrats this election year. Pharma gave the Obama campaign more than three times the money they gave to Republican, John McCain. Compare that to four years ago when drug makers gave Bush twice as much as Kerry. Indeed, over the last decade, the drug industry has spent millions to keep Republicans in the White House as well as in Congress, according to a report in Politico.

Even more revealing about the industry’s left turn is how poorly McCain fared during the primaries. As of the end of September, drugmakers gave $758,724 to Obama, $632,219 to Clinton, and a paltry $284,900 to McCain—just 20% of the Democrats’ total.

This trend was repeated in the Congressional races where, for the first time in six election cycles, House and Senate Democrats reveled in receiving the lion’s share of pharma campaign donations. Clearly, the industry preferred equids over pachyderms this election year.

Does all this reflect a love affair with Obama and the Dems, disappointment with McCain and the Republicans or both?

Factoring into all of this is McCain’s feud with the pharmaceutical industry, which he famously tagged “the big bad guys” and he likes to boast about “taking on the drug industry,” which certainly didn’t sit well with pharma executives.

But are hurt feelings enough to reverse historical trends? The evidence suggests that the issue is deeper and more complicated and is, in fact, tied to a significant shift that is underway in the health care market in this country.

Both parties favored similar drug policies

When looking at the two presidential candidates’ policies, it is hard to understand pharma’s Obama obsession. For instance, headlines during the campaign declared the following: "Obama plan could whack Big Pharma", "Big Pharma could be big loser under Obama health plan", "...neither candidate loves pharma" and this, "Barak Obama and John McCain go to war with Big Pharma."

According to the Boston Consulting Group, Obama favors letting a federal agency set discounted drug prices, which will cut the drug industry’s revenues by a whopping $10-30 billion a year. And the Wall Street Journal’s Health Blog speculates that this would be further exacerbated if private insurers, following the government’s lead—and why shouldn’t they—also insist on paying less for prescription drugs. To make matters even worse, the Dems’ favorite son also favors importation of cheap drugs from abroad.  These are issues that are hotly opposed by the drug industry.

"These are issues that are hotly opposed by the drug industry."

Meanwhile, according to the BCG study, John McCain was “officially silent” on the issue of negotiating drug prices. But, a few years back, he voted against President Bush’s Medicare drug benefit plan partly because it didn’t allow the government to negotiate drug prices.  Furthermore, just like Obama, McCain favored the re-importation of prescription drugs to save money.  Both candidates also endorsed increased use of generic drugs and favor making the exclusivity period of biological drugs as short as possible, all of which pharma steadfastly opposes.

Clearly pharma didn’t feel the love from either candidate, so what explains their swoon for Obama? Did they just close their eyes while kissing up to the presumptive winner?

What are the stakes?

In order to answer this question, we first need to understand basic economics of health care in the US. This country has long favored a free market model for health care, believing that this leads to increased consumer choice and promotes the production of new medicines. A big new drug is reckoned to cost $800 million to develop and the drug giants argue that they need the higher profits from the US free-market in order to drive the R&D required to develop these expensive new drugs and therefore protect their product pipeline and future revenue.

It is said that scientific research follows the money and this is no more evident than in Europe which is not free-market driven and regulates drug prices. Europe also is simultaneously steadily losing its pharmaceutical edge to US labs, which generated two thirds of the new drugs launched in the world over the past five years.  So, while the US produces most new drugs, its free market also almost entirely subsidizes the cost of their development from high consumer drug prices. It follows that any reduction in US drug profits will diminish the ability of pharma companies to support future R&D for new drug development. 

Thus, as Motley Fool analyst, Charly Travers, often points out, any US government policy that caps drug costs will reduce both the number of drugs that can be developed as well as the profits for already approved drugs—a double whammy for the pharmaceutical industry.

Unfortunately, this argument is tempered by the troublesome fact that drug prices in the US are rising at a rate of 7% a year, which is difficult to continually absorb. Hence, the political pressure for price controls on drugs in the US has increased to the tipping point where, for the first time, presidential candidates from both parties favored price controls on drugs—a move away from the free market.

A health care monopsony favors the Dems

It seems that big pharma is looking into a gathering perfect storm—blockbuster drugs are coming off patent protection, drying up current profits; a thin product pipeline imperils future profits and the unprecedented specter of government regulated drug prices, which further threatens future profits.  However, there is a glimmer of hope that explains their leftward lean in this election cycle and, ironically, we can thank President Bush’s un-conservative profligacy for this political realignment.

“…we can thank President Bush’s un-conservative profligacy for
this political realignment.”

Historically, insurers have picked up most drug costs, but during the Bush administration, the heaviest burden has shifted to the federal government, which currently picks up about half the tab. Thus, there is a growing shift in the US health care market away from private insurers and toward federal health care programs—a shift that was accelerated by Bush’s expensive Medicare drug plan for senior citizens.  It truly is ironic that this erosion of the health care free market is driven by a Republican President.

The word economists use for a market in which goods or services are offered by several sellers, but purchased by only one buyer, who can dictate prices, is “monopsony.”  It is a word that too often comes with the antecedent modifier, “government.”  But, despite the tremendous purchasing power of the growing government monopsony, US taxpayers right now get no pricing leverage like they do in most European countries and Canada, where the governments negotiate and regulate drug prices. Clearly, this is going to change with a Democratic monopoly in Washington.  This government monopsony will invariably lead to regulated drug prices in the US, moving us away from the current free market, and as explained above, this worries the pharmaceutical industry enormously.

It light of these shifting market forces, it makes perfect sense that drugmakers are beginning to view the US government as their primary future market and, for this reason, they understandably want to make sure that government-run health programs are robust and bountiful. They know that Dems are more likely than Republicans to deliver on this magnanimity, and this explains why pharma cozyied up to Obama and Congressional Democrats, both of which favor more government-run healthcare.

No one ever accused drugmakers of not being pragmatic and it is in the sprit of such pragmatism, coupled with an eye to the future that accounts for pharma making nice to Dems.  But, with liberal Democrats ruling Washington and Republicans likely relegated to passive observer status after the election, pharma’s leftward lean this year could quickly return to the right if the liberal monopsonists take too big a bite out of US drug profits.

Fallout from the Bailout—time for a bake sale at NIH? (by Steven S. Clark)

After bailing out Wall Street, Congress quickly bailed themselves out in a rush to flee Washington before they could be pinned down with the hard questions that are sure to come. One can imagine the contortions involved as the political class raced for the safety of home districts while simultaneously patting themselves on the back—especially after gorging ad libitum at the pork trough.  Lou Dobbs, the CNN talking head, called Congress’s actions last week, “snarky.”

How the bailout of the financial sector, after federalizing the Dems favorite but failed sibs, Fannie and Freddie, will affect federal discretionary spending, which includes R&D funding, in the years to come is uncertain.  But the immediate effect freezes most federal appropriations at FY 2008 levels.

 Although fiscal year (FY) 2009 began October 1, most of the budget remains unfinished—again—with only three of twelve appropriation bills finalized.  Instead of responsibly returning to finish the budget after the bailout package was decided, our Mensches in Congress departed Washington for a combined Halloween/Thanksgiving/Christmas/New Year break, leaving the final 2009 budget decisions in limbo until next year; thereby providing yet another compelling argument for term limits.

Budget freeze hits US research hard

At least our lawmakers had the good sense to authorize a continuing resolution (CR) rather than let the federal government shutdown as it did during the Clinton years. The CR extends 2008 funding for the various programs covered by the nine unfinished appropriations bills so that the government will continue to function, albeit at last year’s levels.   

The three FY 2009 appropriations bills that were passed are included in the CR and provide funding for the Departments of Defense (DOD), Homeland Security (DHS), and Veterans Affairs (VA); all of which receive substantial increases for their R&D portfolios as described below:

• For DOD R&D programs, congress agreed on $82.4 billion, an increase of $3.0 billion or 3.8 percent to an all-time high. DOD’s basic research efforts will increase by a whopping 12.9 percent or $210 million to $1.8 billion.

• The Department of Homeland Security (DHS) received $1.1 billion in FY 2009 R&D funding, a substantial 9.4 percent or $93 million increase over 2008.

• The VA R&D portfolio, after climbing the past two years from emergency appropriations, will continue to grow after a 6.8 percent increase to $952 million.

Meanwhile, all other federal agencies and programs in the remaining nine unfinished appropriations bills will operate at 2008 funding levels until next March, when a new congress will resume work on 2009 appropriations.  At this time, the total FY 2009 investment in research is actually 0.4% greater than for FY 2008. But, when adjusted for inflation, this represents an overall decline in government research spending for the fifth year in a row. 

Moreover, the picture for R&D funding is even bleaker than this because the CR does not count supplemental revenue in its funding formula.  This means that four science agencies that received supplemental funding last June will actually see a budget decrease for at least the first five months of FY 2009. Thus, the National Institutes of Health (NIH) will have a shortfall of $150 million; the DOE’s Office of Science loses $63 million; the NSF begins FY 2009 down $23 million; and NASA will be short some $63 million. There also is no guarantee that the budget freeze won’t actually won’t be extended for the rest of the year after Washington’s bean counters tally up the budget-busting effect of the bailout.

This budget shortfall comes at a particularly vulnerable time for researchers across the country, especially for those funded by NIH who already are saddled with a dismal grant award success rate of 10% or lower.  The current budget crunch, which is the result of Congress’s failure to complete its task on time, means a further reduction in the grant success rate and reduced awards for already cash-strapped researchers.

Playing politics over a mere $21 billion

Why are we in this budget impasse—why didn’t Congress simply complete the FY2009 budget after finishing the bailout?  The answer to this question can be stated in two words—partisan politics. 

Last June, Congress reached a final agreement on an FY 2009 budget resolution, which established a total of $1,013 billion for regular discretionary spending. This was a mere $21 billion, or 2%, more discretionary spending (less when compared to the entire budget) than that requested by the President, who promised to veto any appropriations bills that exceed his request. Rather than negotiate, re-budget or undertake any other statesman-like activity to resolve this impasse and pass a budget for the country, the Democrats in Congress decided to take a powder and put off remaining appropriations decisions until a new President (read Barak Obama) takes office in January, thus bringing the entire 2009 budget process to a halt. Congressional Dems are banking (pun intended) on an Obama victory in order to protect this measly $21 billion for their domestic projects.

So, there the budget sits, frozen and uncertain, stressing further an already distressed research enterprise and all for a paltry $21 billion—a rounding error in a $3 trillion federal budget, as pundit George Will likes to point out.

It is an understatement to say that whoever is President in 2009 will face a difficult fiscal climate. The financial sector rescue just passed by Congress and signed by Bush means that hundreds of billions of dollars will soon be flowing out of the U.S. Treasury to buy mortgage-backed securities. This outflow either will cut further into discretionary spending or will significantly boost deficit spending, or both. Federal agencies, most of which already face frozen budgets five months into the new fiscal year, are left with few clues as to what their final funding levels will look like. The U.S.science and engineering community once again faces many months of waiting to find out what the federal government’s fiscal commitment to R&D in FY 2009 will be.

Maybe they should have a bake sale and a car wash. 

Detailed analyses of FY 2009 House, Senate, and conference appropriations for individual agencies are available on the AAAS R&D Web site.

Who's your mama? (by Steven S. Clark)

Remember Jurassic Park—the Steven Spielberg sci fi flick in which a greedy businessman and his mad-scientist minions reached inside prehistoric amber to extract, and ultimately clone, dino DNA that had been sucked up by a sap-trapped bug? Seem far fetched?

Maybe not so much.

An international team of scientists from Germany, the US, Croatia and Finland just reported in the prestigious journal, Cell, that they had cloned and sequenced the Neanderthal mitochondrial genome. The DNA was isolated from a 38 thousand-year old fossilized leg-bone that was found in the Vindija Cave in Croatia in 1980.

Mitochondria are small bacteria-like structures found inside cells where they function as the cell’s powerhouse—they produce chemical energy that the cell uses to drive its biology. The relevant thing here is that mitochondria contain their own small, characteristic genome that is distinct from, and inherited differently than, the much larger genome in the cell nucleus. In your prototypical maternal/paternal genetic inheritance, a sperm fertilizes an egg and the nucleus of each contains one-half of the genome the embryo will need to function. Upon fusion of the two nuclei, the fertilized egg, called a zygote, acquires the full genome that it needs to function and grow.

In contrast to the inheritance of the nuclear genome from both parents, the mitochondrial genome is solely obtained from the mother. When a tiny sperm, that is not much more than a nucleus with a tail, fuses with the much larger egg cell, the subcellular organelles of the egg provide the necessary machinery to allow the zygote to survive, divide and do its thing. Hence, the zygote’s mitochondria are completely inherited from the mother. This means that by tracking lineage relationships through mitochondrial DNA (mtDNA) sequence analysis one is examining matrilineal descent between different biological species, genera and families. It is a lens into our past to Eve—the mother of us all.

This amazing feat of cloning and sequencing prehistoric DNA entailed careful and painstaking sterilization of the specimen and then, in a sterile room, carefully chipping away the mineralized bone’s surface to uncover small amounts of DNA that had been sequestered within the stone bone.

High tech DNA cloning and sequencing methods were used to unravel a DNA sequence that clearly came from mitochondrial DNA, but whose? Since we don’t have Neanderthals walking around today—no, not even the Troglodytes in Congress—how could the investigators be sure that the DNA was in fact from the bone’s original owner and not from say, the saber tooth tiger that gnawed on it eons ago or even from some plant matter that was trapped in the sediment that encased and fossilized the bone?

Fortunately, scientists have an extensive database of mtDNA sequences from extant humans as well as from many old and new world apes and other non-hominid animals for comparison. Comparing the Neanderthal DNA to this database revealed that the mtDNA clearly had a hominid origin, but was not from any known family of primates. This confers a high degree of certainty that the DNA was indeed from the fossil bone—the scientists were peering through a molecular window into the genetic history of a species that first appeared pre-history!

The first Neanderthal fossil was found in the Neander Valley near present-day Düsseldorf, Germany and the fossil record indicates that they are the closest known hominid relative to humans—closer even than chimps. The DNA sequence confirms this archeological conclusion. Genetic mutations occur at a predictable rate per generation, and once fixed in a genome, are subsequently inherited by the progeny while new mutations continue to appear at the predictable rate; thus, leaving a bread-crumb-like trail to the past from whence we came. From this, one can construct a “molecular clock” with which to estimate how long ago different hominid species diverged and this indicates, with a 95% statistical certainty, that humans and Neanderthals split off from a common ancestor between 520-800 thousand years ago. In contrast, humans and chimps diverged some six million years ago. The genetic data also showed that Neanderthals likely lived in very small numbers; maybe no more than 10,000 alive at any one time; they were in a distinct minority relative to humans.

Anthropologists have long known that Neanderthals and humans overlapped in history as well as regionally, raising speculation as to whether humans and Neanderthals interbred. However, you can rest easy since the Neanderthal mitochondrial genes "were distinctly different to modern humans, suggesting Neanderthals never, or rarely, interbred with early humans." Perhaps that fact is mostly of interest to a prurient anthropologist who has been in the field too long, but it also should still the salacious speculation from the History Channel of illicit communion between the two species. In other words, Great Grandma was not one of the knuckle-draggers, regardless of uncle Ned’s jutting jaw and flat forehead—that is just the luck of the draw from the Homo sapien gene pool and not due to genetic “contamination”.

Another upshot of this study is that the lessons learned about isolating and sequencing antediluvian DNA will be useful for the analysis of the entire Neanderthal genome that will soon come.

Can "Neanderthal Park" be far behind?

Purdue University guilty of misconduct in research misconduct case, by Steven S. Clark

Rusi Taleyarkhan, a professor of nuclear engineering at Purdue University, was found guilty of 2 of the 12 charges of research misconduct by a special scientific panel appointed by the university.  In 2002, Taleyarkhan published papers claiming to have created what was commonly called “tabletop fusion” or “bubble fusion.”

When other scholars found themselves unable to replicate his findings, questions emerged about the veracity of his work. This led to an earlier Purdue probe into Taleyarkhan's research that found no evidence of misconduct.  But, this did not eliminate the swirling accusations and the university capitulated to Congressional pressure to launch a second investigation.

A report from the second investigation, issued Friday, like the report from the first investigation, did not find that any of the original work was falsified. However, it did find that Taleyarkhan was guilty of “gift authorship”, or adding a name to a paper on which the researcher played no role. In addition, the panel also found that Taleyarkhan overstated a claim in a scientific paper that his findings had been independently verified. Taleyarkhan’s lawyer told The Indianapolis Star that his client was considering an appeal.

In other words, this is what transpired: competitors who were unable to replicate the Purdue Prof's research accused him of faking it. Two panels at Purdue looked into this allegation and neither faulted him on his research findings.  Rather, one panel, but not the other faulted him for comparatively minor (important, but minor) infractions that seem unrelated to the original accusation.  And these infractions were only found after very close scrutiny of the Prof's day-to-day activities.

Put all research professors to the same stringent test and you will find similar minor problems of gift authorships, hyperbole, negligence in attribution, etc.  Put anyone in any profession to such a stringent test and you will find similar minor problems.

To be sure, people need to be transparent in their professional lives where the appearance of proper behavior is just as important as behaving properly.  We need to have people believe in our research and have confidence in our findings and when we give an appearance of sloppiness, even if we are not sloppy, that confidence is lost.

This applies not just for individuals, but for institutions as well. It certainly appears on the surface that Purdue went witch hunting in order to find or manufacture anything against Taleyarkhan. Even if this is not true, the perception of the University's behavior in this case is very troubling.

Was Purdue going to try the guy until they could find something to pin on him?  To what extent would they have gone to do this?

Committee 1 finds no fault.  Committee 2 finds just a little bit. Which is it?  What about committee 3?

This is double jeopardy.  What a terrible blow for due process in the academy and Purdue's faculty is the big loser here.
________________________________________________________________________________________

© 2008 Steven S. Clark, PhD, some rights reserved. Articles contained herein, are meant to be distributed freely to interested parties. However, any excerpts from any article must credit BioScience Biz.

Disclaimer: The authors used their best efforts in collecting and preparing the information published herein. However, neither Steven S. Clark, nor other authors, assume, and hereby disclaim, any and all liability for any loss or damage caused by errors or omissions, whether such errors or omissions resulted from negligence, accident, or other causes.

 

 

Wisconsin’s $750 million biotech investment could use better vision, by Steven S. Clark

In 2004, the nation took notice as California and Wisconsin independently announced major investments in stem cell and biotechnology research. In California, voters approved Proposition 71, a massive $3B commitment over ten years to fund stem cell research. In Wisconsin, Governor Jim Doyle announced a $750 million state investment in biotechnology in order to help the state maintain a leadership position in the life sciences. Four years later, let’s take a look at what is going on inside Wisconsin and around the country to gauge just how well Wisconsin’s biotech leadership is holding up.

Home cooking—Wisconsin’s biotech investment

The cornerstone of Wiscon’s $750M biotech investment is the $150M Wisconsin Institute of Discovery (WID). WID is a partnership between the state, the Wisconsin Alumni Research Foundation (WARF) and a generous donation from John and Tashia Morgridge, each of which contributed $50 million to build a new public/private hybrid research building on the UW-Madison campus. Some of Doyle’s total came from the public sale of Blue Cross Blue Shield of Wisconsin, which had been in the works quite awhile before Doyle’s announcement. The total also includes $134M and $132M for new additions to the UW-Madison School of Medicine and Public health and to the Medical College of Wisconsin, respectively—funds that also had been raised much earlier and that included substantial private contribution..

By my count, of the $750M, $421M comes from non-state sources or is money that already was earmarked for medical school buildings when Doyle made his announcement, leaving about $330 as Wisconsin’s total commitment to life sciences since 2004—a tidy sum to be sure, but not as impressive as it was made to sound. This is about what California will spend on stem cells each year for the next ten years.

More revealing is what this money is buying. A significant portion clearly is going for bricks and mortar in order to expand and modernize the research infrastructure in Madison and Milwaukee. A substantial amount of the money from the sale of BCBS goes for local public health and education efforts across the state. It is disingenuous to add this money into the total of a biotech initiative.

Even though ground has just been broken for the WID and the building won’t be finished until 2010, we can get a glimpse of the research the Institute will support from the $3M recently awarded for Discovery Seed Grants. These Seed Grants will support the following research:

• finding a diagnostic test for a common causes of infertility in women.
• understanding cognition and the effects of Ritalin in the brain.
• more efficient production of embryonic stem cells.
• finding new drugs that inhibit cancer cells from spreading to other locations.
• improved healing of persistent wounds.
• high-tech screening for drug candidates that can dock to critical disease-specific receptors on cells.
• developing micro-optical lenses that can be fine-tuned by environmental factors.
• finally, there also is a project to find improved ways to teach African American children from low income families to speak proper English.

While each of these projects, individually, are certainly very interesting and address important questions, it is hard to see any overarching theme in this disparate collection of projects. Was there any strategy behind selecting these projects other than that these were the ones that rose to the top of the pile of the potpourri of proposals that were received?

Case in point--as important as the research likely is, how teaching minority children to speak proper English fits into a biotech initiative is utterly befuddling. The micro-lens project may not have much life science relevance as well.

The impression from all of this is that the research component of Wisconsin’s biotech initiative lacks a critical focus that a rather small investment cannot afford. When competing with billion dollar initiatives, a smaller contender needs to clearly define its specific strengths, identify important opportunities related to those strengths and proceed in a focused fashion to capitalize on strength and opportunity rather than spread the largesse willy nilly. But, it appears that Wisconsin soon will have a fabulous, brand spanking new research facility staffed by a mish mash of researchers who will have little in common to talk about with each other.

For comparison, let’s take a look at what Wisconsin’s competition has been up to recently.

Looking Westward--California

While Wisconsin’s $3M in Discovery Seed Grants was given to 8 disparate research efforts, not all of which relate to biotechnology, the California Institute for Regenerative Medicine (CIRM) has so far approved 206 grants for more than $554M, all focused on stem cell research and regenerative medicine. These grants include money to support and train 169 new stem cell scientists and clinical fellows, 22 grants to launch the research of new faculty, funds for 73 seed grants to test highly innovative ideas, and awards for 28 comprehensive grants to senior stem cell scientists.

More importantly, on top of their stem cell meta-focus, the California initiative recently finished a round of grant awards strategically concentrated on developing new stem cell lines. The research programs supported by these California awards will go to find better ways to reprogram adult cells into stem cells and to develop clinical-grade stem cell lines that can be used to treat patients. Some of the projects will develop disease-specific stem cell lines in order to model cell development in Parkinson’s disease, amyotrophic lateral sclerosis (ALS) and cardiovascular disease. This represents a beneficial mix of complementary projects so that the whole of California’s research initiative is greater than the sum of the individual projects.

California made 16 of these awards for a total of $23M, which comes to $1.44M/award compared to Wisconsin’s average of $375,000/award--26% of the California average.

Like the first round, the next round of CIRM research awards will also be strategically focused, but on forming disease-specific teams of researchers and clinicians to develop stem cell therapies for human illness. From the preliminary applications that have been accepted, these teams propose to develop stem cell therapies for diabetes, eye disease, osteoarthritis, wound healing, stroke, heart disease, muscular dystrophy, AIDS, Parkinson’s disease and certain blood diseases. CIRM indicates that successful proposals will include a plan for an investigational new drug filing with the FDA at the end of the four or five year project.

Wisconsin should especially take notice that these disease-specific team projects involve cross-functional teams of scientists and physicians, often from multiple California public and private institutions. The teams can also include partnerships with private biotech and pharma companies across the US, as long as the company has an office in California. Clearly, California is creatively leveraging its resources to not only support research, but also to ensure that the research is translated into business and moves into the clinic.

Compare California’s inclusive, collaborative team approach to Wisconsin’s singular focus on UW-Madison with the WID. While Wisconsin’s 8 Discovery Seed Awards do involve research teams, the teams only come from UW-Madison. These awards fail to take advantage of the growing private biotech sector in Southern Wisconsin and the scientific talent that can be found at other institutions across the state such as UW-Milwaukee, the Medical College of Wisconsin and the Marshfield Clinic.

In other words, California has purposefully focused its research efforts, while simultaneously encouraging broad public and private partnerships across the state. Wisconsin has done exactly the opposite by funding a broadly unfocused research portfolio restricted to a single institution.

California has positioned itself to get more “bang for the buck” than Wisconsin will for its investment.

It doesn’t stop there—the competition is getting more intense

In a 2004 press release, Governor Doyle said that California’s $3B stem cell investment, “…will not diminish Wisconsin’s role; if anything, there will be a synergy between our two states." However, time shows that California prefers to synergize elsewhere.

For example, the Canadian Institutes of Health Research announced in a recent press release that it will join forces with California to focus on cancer stem cell research. Toward this end, Canada pledged $100M ($98.9M USD) to the Cancer Stem Cell Consortium, a partnership of academic, business and government agencies, which will work with CIRM.

On top of that, CIRM is actively seeking partnerships with the US federal government as well as with other nations in order to turn their ten-year commitment into a sustainable venture. Indeed the CIRM is working on a deal with the Australian state of Victoria and last year, the Canadian   province of Ontario ponyed up $30M for cancer stem cell research linked to CIRM. 

 Now look Eastward—Maryland, Massachusetts and New Jersey

Wisconsin does not only have to worry about competition from California--Massachusetts,  Maryland and New Jersey have or are planning major financial forays into the biotech field. In mid-June, Maryland Governor, Martin O’Malley announced a plan to provide $1.1B over the next ten years in state incentives in the form of tax credits and grant programs for the state’s biotech industry, while the state’s pension board will invest an additional $500M, bringing the total to $1.6B. The goals are to build a biotech center, finance capital projects and to make equity investments in start-up biotech companies—an intriguing and innovative idea.

It used to be that angel and venture investors covered this earliest and critical stage in biotech development that is euphemistically called the “valley of death”--a nod to the difficulty researchers have commercializing their ideas. But recent trends show that investors are increasingly reluctant to invest in nascent companies—they want to see prototypes and experienced teams in place before plunking down their money. Therefore, equity funding from states promises to meet an increasingly critical need for commercializing emerging biotechnology and this tactic could very well generate a nice return for Maryland —if it is approved by the state legislature.

Not to be outdone in the state bidding war for biotechnology, Massachusetts Governor Deval Patrick recently signed legislation to allocate $1B over ten years to fund the State’s life sciences industry. This includes $250M in tax incentives to support the growth of biotech companies, the same amount to fund research and $500M in infrastructure.

Patrick said it takes "political will and courage to make those long-term commitments" and admitted that his state's funding commitment is, in part, a defensive measure to ensure that Massachusetts’ universities, companies and research institutes retain top scientists and biotech companies.

Patrick’s candid admission underscores the intensity of the competition for science talent and resources in which Wisconsin wants to successfully contend. Further underscoring the high stakes in these biotech funding wars, Patrick claimed that over the next ten years, Massachusetts' support of the biotech industry will create 250,000 new jobs. In this light, it is illustrative that Massachusetts’ commitment to the biotech industry heavily factored into the decision of the regenerative medicine company, Organogenesis, Inc, to expand it operations in the state rather than elsewhere.

Meanwhile, in New Jersey, legislation was introduced in late June to establish a pioneering public-private vehicle for state funding of stem cell research with venture capital. A press release said that the bill will allow private investors to contribute up to $500M over five years to fund such research. To encourage participation, investors would be granted tax credits equal to their investment, but only if a funded research project failed to repay the loan. In order to obtain funding, researchers would submit loan applications to the state’s Economic Development Authority. Both non-profit and academic labs would be able to apply for a stem cell research loan.

What’s a state in fly-over country to do?

Clearly, Wisconsin has a very credible biotechnology research enterprise thanks to the huge bioscience community at UW-Madison. The state’s biotech footprint is even more impressive when private biotech companies and institutions other than the UW-Madison are included. Despite this research muscle and recent infusion of state money, Wisconsin is missing a narrow and critical opportunity to capitalize on its strengths because it lacks the vision and creativity seen in the efforts of other states.

Wisconsin could learn from California and make a much more resolute effort to strategically focus on developing specific biotech strength, be it stem cells or something else. Wisconsin also could learn from California, Massachusetts and New Jersey about creative leveraging of public and private resources to boost, not only academic biotech research, but biotech business as well. After all, the best research, if not translated into successful businesses, does nothing for the people, the state or the economy.

On average, across the country, every new biotech job generates almost 6 additional jobs in the community. Salaries in the biotech industry average a whopping 68% higher than other private sector jobs. This is the return that Wisconsin can expect to realize by wisely investing its resources in biotechnology. However, the latest data show that Wisconsin falls below average in both of these metrics, yet we have an above average per capita infusion of federal research dollars.

Wisconsin clearly has room to realize a better return on its investment.

_______________________________________________________________________________

© 2008 Steven S. Clark, PhD. Disclaimer: The authors used their best efforts in collecting and preparing the information published herein. However, Steven S. Clark, nor other authors, do not assume, and hereby disclaim, any and all liability for any loss or damage caused by errors or omissions, whether such errors or omissions resulted from negligence, accident, or other causes.

Articles contained herein, are meant to be distributed freely to interested parties. However, any excerpts from any article must credit BioScience Biz.

The brave new world of stem cells and human cloning, by Steven S. Clark

One of the great promises of embryonic stem cell research is being able to use human cloning to derive stem cells that carry genetic defects associated with myriad maladies. These cells can be used to study the development of tissues that are affected by genetic abnormalities and used as tools for testing new therapies for intractable genetic diseases.

The way that this works is that a researcher derives an embryonic stem cell line from someone with, say Parkinson’s disease. These stem cells can be coaxed into developing into the dopamine-producing neurons that are defective in patients with the disease. Then, a number of different things can be done. For instance, the development of these diseased neurons can be compared to the development of normal neurons in well controlled environments and, hopefully, yield new information on the origins and progression of the disease. Alternatively, the Parkinsonian neurons can be used to test new approaches for treating the disease.

Thus, cloning and derivation of disease-specific stem cells promises to be a powerful and novel tool for studying certain types of cardiovascular disease, certain cancers such as neuroblastoma, Alzheimer’s and Parkinson’s disease, amyotrophic lateral sclerosis (ALS or Lou Gehrig’s disease), metabolic problems such as diabetes, and so on.   

Ethical concerns of cloning human embryos notwithstanding (I am working on a column on this topic that will be posted at a later date), a confounding technical problem is where will researchers find the eggs necessary for the nuclear transfer cloning procedure (the procedure used to clone Dolly, the sheep)? Obtaining human eggs is done routinely at in vitro fertilization clinics, but it does involve hormonal manipulation of young women and a somewhat invasive procedure to harvest the eggs. Who would volunteer for this just so a scientist can do lab research? How many eggs will we need to all the research scientists want to do and are there enough women donors to supply the research needs?

Researchers in England are taking a new approach to deal with the problem of egg supply. They propose to undertake nuclear transfer cloning using eggs from pigs and chromosomes from a human with the desired disease in order to create animal-human hybrid stem cells. A UK regulatory agency recently licensed a laboratory to create human-pig embryos in order to study heart disease.

In fact this is the third animal-human hybrid embryo license to be issued by the British Human Fertilisation and Embryology Authority. In an article just published in the British newspaper, The Telegraph, an HFEA spokesman said it had just approved an application from the Clinical Sciences Research Institute, University of Warwick, for the creation of hybrid embryos. This effort at the University of Warwick is led by Professor Justin St John. "This new license allows us to attempt to make human pig clones to produce embryonic stem cells," he said.

"We will take skin cells from patients who have a mutation for certain kinds of heart disease (cardiomyopathy, which makes the heart lose its pumping strength) and put them into pig eggs after their chromosomes have been removed. We will then make embryos so that we can attempt to derive embryonic stem cells which will allow us to study some of the molecular mechanisms associated with these heart diseases.

"Ultimately they will help us to understand where some of the problems associated with these diseases arise and they could also provide models for the pharmaceutical industry to test new drugs. We will effectively be creating and studying these diseases in a dish.

"But it's important to say that we're at the very early stages of this research and it will take a considerable amount of time. There is still a great deal to learn about these techniques and much of our early work will involve understanding how we can make the hybrid cloning process as efficient as possible."

The study is aimed at understanding the way the cell’s power-producing structures, called mitochondria, are passed from egg to embryo. Mitochondria contain their own small genetic program that produces many of the proteins these organelles need to power cells. Therefore, in the hybrid stem cell, the mitochondria will mostly come from the pig egg, and the researchers will do experiments in order to ensure that the trace of human mitochondria takes over, not least because it is designed to work with human nuclear DNA.

"The key thing we are doing is trying to create stem cells without any animal mitochondria in them. So even though these hybrid embryos normally have…animal mitochondria, we are hoping to create hybrid embryo cells that would have human chromosomes as well human mitochondrial DNA." The reason is that, as the team puts it, "mixing of these two diverse populations of mitochondria can be detrimental to cellular function."

Other research teams in Newcastle and London are also creating human-animal hybrid stem cells. The former have already created hybrids with cow eggs to study genetic regulation in early development, the latter made hybrids with a range of species to generate stem cells from people with neurodegenerative disorders.  Meanwhile, Chinese researchers in Shanghai have reported success in creating human-rabbit hybrid stem cells.

Such research is not allowed in the US, at least in federally-funded labs. But, this does not seem to stop this field from going forward world-wide. Are we in a brave new world, or are we making a Faustian bargain?

Read more on human-hybrid stem cells:

Hybrids: separating hope from the hype

Questions answered on animal-human embryos

Embryo research: a source of hope or horror?

Is drinking red wine the same as going on a diet?

Research says maybe so.

When considering factors that affect health, most people think about fatty diets, sun exposure, smoking, alcohol consumption, etc. But, research clearly indicates that one of the most important factors in quality of health is the simple calorie, which seems to one of the last health factors that people mention.

Everyone knows that obesity is associated with myriad health problems from cardiovascular disease, diabetes and stroke. Recent studies also link obesity to neurological problems such as Alzheimer’s disease. Obesity is caused by several factors including poor diet, sedentary lifestyle as well as genetic and metabolic issues. Certainly, caloric intake is a factor in obesity, but compelling research in rodents has shown that even a diet that does not lead to obesity may play an amazing role in age-related loss of function in the skeletal muscle, brain and especially the heart. When animals are restricted in caloric intake, but allowed normal levels of nutrients, vitamins, etc, their lives are significantly prolonged and their bodies retain a youthful physiology much longer than animals fed a regular diet.

I’ve seen the research data of caloric restriction on the musculature of the heart and the results almost gave me chest pains thinking about what my heart must look like in middle age.

Studies in several labs, including one recently reported by UW-Madison’s Tomas Prolla and Richard Weindruch, show that mice that are fed a component of red wine called reservatrol, along with a regular diet, showed healthier physiologies than mice who were not fed reservatrol. Significantly, the mice fed reservatrol and a regular diet, were as healthy as the mice on the calorie-restricted diet. In other words, feeding reservatrol to mice mimicked the beneficial effects of caloric restriction.

Both, Weindruch and Prolla, admitted to taking reservatrol supplements. But is this a good idea? Read more about this line of research here.