FOUR HORRORS: Stroke, Diabetes, Blindness, ALS—and How Embryonic Stem Cell Research May Defeat Them
By Don C. Reed
Before I met the monster on the road, I had been on my way South to Los Angeles for the Independent Citizens Oversight Committee (ICOC). This was an especially important meeting at which the big disease team grants would be decided, as much as $20 million each, loans or grants. Some projects would go forward, others would die.
My cell phone rang.
Pulling off the freeway and fumbling through my suitcase (keep ringing, keep ringing!), I found the phone, opened it, recognized the numbers on the screen.
Dr. Hans Keirstead…. I dreaded what the voice might say.
He had a project in question: a way to use embryonic stem cells to fight Spinal Muscular Atrophy: important not only to the children who suffer and die from this terrible condition, but to the entire field of research. Some of the problems he was taking on in this project would affect everyone.
But the funding had been turned down.
The problem, as I saw it, was procedural: the official cutoff deadline for new project information was April… Since the cutoff date, Dr. Keirstead had gotten a ton of new information, some 9,000 pages of it, including the results of animal testing, and much correspondence with the FDA: important stuff which I felt sure would change the opinions of the reviewers—but they had not seen it.
There was a process for appeal, and I had been encouraging him to use that process to try and overturn the denial of funding.
As a member of the public I have a First Amendment right to talk to just about anyone, (including state employees like the ICOC, who enjoy the equally valid right to ignore me) and I had spoken with about half of the 29-member board who would be making the final decision. (I emailed first, asking if we could talk. Those who did not object strongly enough got a phone call.) Most of them said the same thing, that it was an uphill battle, (like everything else in this business) but they would listen at the meeting with an open mind. That was all anybody could ask.
Could the potentially game-changing new information be included?
I believe the National Institutes of Health (NIH) has ways that late-breaking news can be added to proposals, and we should consider incorporating those procedures into our own bylaws. But in the meantime we had the “extraordinary appeals” process, and if the scientist was willing–
“I decided not to go forward with the appeals process”, said Hans Keirstead.
Internally I said something unprintable. I had invested maybe seventy hours in the struggle to understand and defend this one project, and was loaded for bear. But–
“I understand their decision,” he said, “If I had been a reviewer, and only got what I was able to give them in April, I would probably have done the same thing…”
And so, on a technicality of timing, a grant would not be given: what might have been a hugely important embryonic stem cell project would not be funded by us.
Well. Adjusting to the new reality, the fight that would not happen, I pulled back out onto the empty stretches of Highway I-5, just past Bakersfield, before the L.A. grapevine. Since gas prices skyrocketed, there are far fewer vehicles driving: I was almost alone on the road.
In the distance was a blur across the road. I paid it no mind, thinking it some object that would soon be gone, went back to my day-dreaming,now my mind was free to wander.
The ground in that area is desolate, barren. A huge road-side sign blamed it on the government—“this dustbowl brought you by Congress”—apparently the same people who put up the sign, “where water flows, food grows” beside the canal.
Translation: Southern California wants more of Northern California’s water.
I thought about the movie, CHINATOWN, based on a true story, the multi-gazillion dollar consequences of a water rights decision, made by a government board…. (You can read about it in “Rivers in the Desert: William Mulholland and the Invention of Los Angeles”, by Margaret Leslie Davis.)
The real culprit was also at the side of the road—cotton…. raw material for underwear, cotton is a robber of water, thieving moisture more greedily from the soil than any other crop.
The blur in the distance grew, into something huge and dark across the freeway.
A vast wall of dirt, suspended in the air.
Bizarre and ugly tendrils reached out from it, coiling and extending, like a special effects monster, creature of darkness, snatched from the ground…
There was no way around, no time to think, just step on the brakes as hard as I could without losing control, reducing speed from 70 to 30, entering the wall…
Whooooshshshsh…. Darkness. I could only hope the road went straight ahead, because I could see nothing…
Then, the other side, my car emerging filthy, windshield wipers scraping dirt, brown sky ahead, the sun glaring palely.
It being almost Halloween that day, thoughts of monsters entered my mind, Godzilla coming to stomp some poor city again.
But real-life horrors come at us every day, rearing up out of the unexpected, coming to destroy our lives.
Consider just the financial costs of four horrible—and presently incurable– medical conditions: Stroke. Diabetes. Blindness. ALS.
In one year, stroke costs America $56 billion in medical costs.
Vision problems (of which macular degeneration is a huge component)– $51.4 billion.
ALS—I cannot find an overall figure, but it may cost two hundred thousand dollars–for one patient, per year. My rough guess (based on 20,000 patients) would be $4 billion.
Add that up: $285 billion a year—for just four medical conditions.
We spend so little fighting back against these real-life horrors: as if Godzilla attacked New York– and the military got a nickel for a slingshot to fight it.
Opponents complain about the expense of California’s entire stem cell program– which has a budget of only $295 million a year—roughly one one/thousandth of the cost of just those four conditions. If we can help alleviate or cure even one of those devastating conditions, it would be the greatest bargain in medical history.
Fast forward to the meeting.
Two dozen leaders of the ICOC sitting at a square of four tables. Champions all. People like Ed Penhoet, just chosen to be a special biomedicine adviser to the President. (Dr. Alta Charo, one of our advisors, was also recently honored by being selected to advise the FDA!) Bob Klein was recently honored by Research!for America, receiving the Gordon and Llura Gund Award for medical research advocacy. Over there was Television’s Leeza Gibbons, head of her own organization to fight Alzheimer’s, and to her right was Sherry Lansing, former President of Paramount Motion Pictures, battling for cancer research—a book could be written about just the members of this board. Not a political hack among them.
Today, they would be deciding the biggest medical research grants in our history.
Before the meeting began, $210 million had been set aside (with a buffer of an additional $30 million) for the disease team grants.
To my amazement, the review board (a separate panel made of scientists from different states and nations, none from California) had recommended cautiously—$189 million.
What? We were not going to spend the money budgeted to fight disease?
Naturally, being of an age when everything reminds me of something else, I had to step up to the microphone and give my two cents worth, telling a true story which seemed applicable.
A settler in old West times was found dead after an Indian attack. Arrows were stuck all through him—and, clutched uselessly in his hands, a single-shot rifle, its one bullet unfired…
I would have fired that bullet, I said. After that, I like to think, I would have swung the rifle as a club until it broke, and then looked around for rocks to throw.
We are here to fight terrible diseases and conditions. We have the money, let’s go for it.
“But only when the science is first-rate,” Bob Klein put in quickly.
At the end of two days careful consideration, the ICOC approved the expenditure of just shy of $230 million.
Our money was on the table, the bets were made. Fourteen grants…
Here came something ironic.
Guess which got more money– embryonic or adult stem cell research?
Prop 71 was designed to be sure the best science was funded, at a time when President George Bush’s ideological convictions were blocking the advance of embryonic and other advanced forms of stem cell research.
Today, adult stem cell research (often combined with gene therapy) got the bulk of the funding. The opposition of course is playing this up for all they can, trumpeting this as “proof” that they were right all along, and there is no need for hESC research.
Let’s look a little closer.
These are grants for team projects which had the best chance to advance—in just four years— to a phase one clinical trial for an “incurable” disease or disability.
Remember all the advantages adult stem cell research has had: a fifty year head start, massively preferential funding from Washington, zero political harassment—contrast that with the virulent opposition from the religious right and its allies in state and national capitols, not to mention near strangulation of funding– it would be natural to assume that all of these ready-to-go grants would be for some form of adult stem cell research.
But that is not quite how it worked out.
Remember the four “monsters” mentioned earlier– stroke, diabetes, ALS, and macular degenerative blindness?
Naturally, being California, we are going after all four– and the weapon of choice to fight them?
Embryonic stem cell research.
With every option available, California chose embryonic stem cell research for these four horrific conditions. Why?
Because California is going for the best method to find a cure. Adult, embryonic, iPS—we seek to save lives and ease suffering. Unlike our opponents, we do not select medical research by its political acceptability.
Personally, I believe that embryonic or the embryonic-like reprogramming (or SCNT, which has a lot more potential still to be explored) will be the way to go: that projects based on adult stem cells will eventually need to be re-done with the more powerful hESC or reprogramming approach.
Even so, one of the projects I spoke up most vigorously in favor of was an adult stem cell project, Dr. Irv Weissman’s attack on leukemia.
Why? Because not only do I (and the scientific community!) have enormous respect for Dr. Weissman, but also because I know I can be wrong. If an adult stem cell approach turns out to the best way to help people, of course I’m for it.
That’s what medical research advocacy is about: to find out—and fund—the best.
Take a quick look at the four embryonic stem cell projects. This information comes from the website of the California Institute for Regenerative Medicine website: www.cirm.ca.gov. The reports are also available through the clickable list at the bottom.
I have shortened them (thirty-some pages down to 3), for ease of reading. Other than that (and parenthetical insertions like this one) these are the actual words.
Description: stroke occurs when a blood clot blocks a blood vessel in the brain, and cuts off blood flow. Brain cells begin to die…(which) can cause permanent loss of motor control, movement and cognitive abilities… (imagine being paralyzed, losing the ability to speak, perhaps even unable to think properly—dr)
Quick Fact: Stroke causes more serious long term disabilities than any other disease.
Disease Team Award: The Stanford University-led team (Primary Investigator Dr. Gary Steinberg) plans to use cells derived from human embryonic stem cells… to improve recovery in the weeks and months following a stroke.
The team will be…(turning) embryonic stem cells into neural (nerve) stem cells…normally found in the brain. When these…cells are transplanted into the brains of mice or rats one week after a stroke, the animals are able to regain strength in their limbs.
Based on these findings, the Stanford-led team proposes to further develop these neural stem cells into a clinical development program for stroke in humans….
MACULAR DEGENERATION BLINDNESS
Description: Macular degeneration (a disease of aging) gradually destroys sharp central vision, making it impossible to see faces, to read, or to drive… deterioration of the retina…
Underlying (the retina) is a single layer of cells (retinal epithelial cells, RPEs)… that provide support, protection and nutrition…to the retina. Degeneration of (these support cells) leads to … vision loss.
Quick fact: Age-related macular degeneration (AMD) affects more than 1.75 million Americans. There is currently no cure….
Disease Team Award: Led by researchers at the University of Southern California, (the team will) …use human embryonic stem cells to replace dysfunctional or destroyed (RPE) cells to slow or reverse the disease. They plan to coax human embryonic stem cells to differentiate into… (RPE) cells that can be transplanted into the eye.
The replacement cells will function normally to support to and protect the…retina and prevent further degeneration and vision loss.
AMYOTROPHIC LATERAL SCLEROSIS (ALS)
Description: ALS, also known as Lou Gehrig’s disease, is a progressive disease that involves the death of motor neurons (which are) cells in the brain…and spinal cord that connect directly to muscle. As these cells die, signals from the brain to the muscle are cut off and patients lose motor control…(leading to) paralysis…and death. …. People with spontaneous ALS (one of two kinds of the disease) have higher levels of… glutamate in the spinal fluid… Scientists suspect glutamate may be involved in (the cause of) ALS…
Quick Fact: There is no cure for ALS, but there is a drug, called riluzole, that extends life by a number of months(3-6). Riluzole decreases… glutamate, and in turn, decreases damage to neurons…
Disease Team Award: The team at the Salk Institute for Biological Studies plans to protect surviving neurons from further degeneration in people diagnosed with ALS. The strategy involved targeting (astrocyte) cells which…surround and protect neurons. (Astrocytes regulate glutamate.)
The team intends to grow human embryonic stem cell-derived astrocyte precursors that will be transplanted… into the spinal cord environment to prevent further…degeneration caused by ALS. The work…should be effective in (both varieties of) ALS.
TYPE 1 DIABETES
Description: People with type 1 diabetes, known as juvenile diabetes, cannot produce insulin… which (normally) helps take up sugar from the blood. … Although it is possible to replace missing insulin with injected insulin, people with diabetes still tend to have higher than average blood sugar levels. This excess sugar damages the retina, nerves, kidney and blood vessels. Because of this damage, people with diabetes often have cardiovascular disease, kidney failure, blindness, and (may) need amputations due to wounds that can’t heal.
Quick Fact: (approximately) 15,000 youths in the Unites States (are) newly diagnosed with type 1 diabetes annually.
Disease Team Award: Dr. Jeffery Bluestone and the Novocell, Inc-led team has developed methods to make large-scale batches of replacement beta cells from human embryonic stem cells (hESC).
… these hESC-derived beta cells cure experimental disease in mice and rats. ..The team now plans to complete the manufacturing, efficacy, safety testing required to generate the necessary data for FDA approval to test in Phase 1 clinical trials.”
End of quoted materials.
So. Despite the enormous advantages given to the field of adult stem cell research by the previous administration (which favored it over embryonic more than 7-1 in terms of grant money), and although adult stem cell research has been around since the middle of the last century, compared to embryonic which was isolated just 11 years ago—even so, hESCr was chosen to attack these four horrific incurables.
I think it was Dr. Kevin Eggan of Harvard who came up with a great line recently. He was asked if there was still a need for human embryonic stem cell research, (hESCr) since there were other options, like iPS, the skin cell reprogramming, which he helped develop.
Eggan answered, (if memory serves) that of course we still needed human embryonic stem cell research, because everything else was an imitation—and hESCr was the real thing.
So what we do we need next?
How about an RFA (Request For Applications) for a major grant to fund actual clinical trials? Before any cures can reach people, they must be tested, and this can cost a bunch of money—so far, Geron (back on track for human trials next year, btw) has spent about $45 million, and will probably spend that much again—we need a way to support these crucial tests—maybe matching grants?–so good ideas will not stay locked up in the labs.
And if Dr. Keirstead’s SMA work finds enough funding elsewhere, (which I am confident it will, although slower than if we had been able to fund it through CIRM), maybe his project will be eligible for that one…
At the two-day meeting, there was far too much to talk about—the international advances alone have far too much substance to be summed up in a short article.
For me, there was one moment when it all came together, and it happened right before the meeting official begins.
CIRM person Melissa King led the pledge of allegiance. She began it as she always does: “please stand, if you are able”.
I never hear those words without getting a little misty-eyed: not only in pride for my state and our nation, which make possible this magnificent effort: but also reminding me why we are here.
Below is the official write-up from the California Institute for Regenerative Medicine, which I lifted from their website. (They of course have no connection to my opinions.) Under that is a clickable list of the 14 projects funded, in case you want an up-close look. (I underlined and bold-printed the word “human embryonic stem cells” on the title of the four hESCr projects I talked about.)
Oh, good news, the lawsuit against America’s embryonic stem cell research program was thrown out! More to follow soon. It is an important decision, which may (IMHO) affect anti-research legislation across the country…
Don C. Reed
CIRM, the UK and Canada Award more than $250 Million to Accelerate the Pace of Bringing Stem Cell Therapies to the Clinic
October 28, 2009
Novel funding mechanism speeds the path of research
Los Angeles, Calif., October 28, 2009 – The California Institute for Regenerative Medicine, the state stem cell agency, and two international partners awarded more than $250 million to 14 multidisciplinary teams of researchers in California, the UK and Canada to develop stem cell-based therapies for 11 diseases. The Disease Team Research Awards include approximately $8 million from the Medical Research Council, UK, and approximately $35 million from the Cancer Stem Cell Consortium, Canada, to fund the international portions of the collaborations.
CIRM’s 29-member Governing Board voted to approve funding for the four-year grants, which mark the first CIRM funding explicitly expected to result in a filing with the FDA to begin a clinical trial. The Disease Team Research Awards fund research teams that include basic scientists and clinicians from both academia and industry. These collaborations speed the process of establishing clinical trials by insuring that clinically relevant issues are considered early and avoiding potential safety issues being discovered late in the process.
CIRM President Alan Trounson said the pace of the Disease Team projects stands in contrast to the decade or more that’s usually required to reach clinical trials. “Scientists have talked for years about the need to find ways to speed the pace of discovery. By encouraging applicants to form teams composed of the best researchers from around the world we think CIRM will set a new standard for how translational research should be funded,” he said.
Each team will be actively managed by CIRM and the agency’s international partners for those teams with cross-border collaborations. Decisions to move forward with the project will be made at key points in the development cycle.
“This unique partnership is another opportunity for the people of California to lead the way in this important research and advance potentially life-saving science,” said Governor Schwarzenegger. “These grants will help unite some of the best scientists throughout the world, including right here in California, to find new therapies and cures for people suffering from chronic and life-debilitating diseases. I am proud California remains at the forefront of this innovative research and I look forward to the results of this international collaboration.”
“This initiative is bringing together the leading minds in cancer and stem cell research from Canada and California,” said Dr. Morag Park, Scientific Director of the Institute of Cancer Research, part of the Canadian Institutes of Health Research (CIHR), the Government of Canada’s health research agency. “CIHR, in conjunction with Genome Canada and through the Cancer Stem Cell Consortium, is proud to fund Canadian Scientists in this cross-border collaboration that will engage scientists from many disciplines, combine resources, technologies and knowledge to find more effective treatments for leukemia and solid cell tumours.”
Sir Leszek Borysiewicz, Chief Executive of the Medical Research Council: “The partnerships that have been established between the UK and CIRM have brought us closer to delivering the promise of stem cell treatments for debilitating conditions. We hope these projects will accelerate treatments to early clinical trials, eventually leading to a direct benefit for people suffering from age-related macular degeneration, which up until now has been regarded as incurable and also acute myeloid leukaemia. The MRC has led the way for UK translational researchers and together with our partners at CIRM we look forward to realising the full potential of stem cell research”
Other diseases being targeted by the teams include HIV/AIDS, type 1 diabetes, damage from heart attack, sickle cell anemia, amyotrophic lateral sclerosis also known as Lou Gehrig’s disease, and epidermolysis bullosa, a hereditary life-threatening condition of the skin’s connective layer. The 14 awards will go to seven not-for-profit institutions and one for-profit institution. The award to the one for-profit grantee will take the form of a loan.
“CIRM’s loan program will recycle money back into future awards and leverage the voter’s commitment to the field,” said Robert Klein, Chair of the CIRM Governing Board. “In providing stem cell funding in the form of loans, CIRM is able to fund more science and make a more significant impact on the speed of bringing new stem cell-based therapies to the people of California and the world.”
Other ICOC Business
The board also voted to approve an update to CIRM’s on-going strategic plan. The current plan, approved in 2006, anticipated a slower pace of research toward potential clinical applications. The revision proposes an increased emphasis on moving safety tested candidate therapeutics to the clinic and encourages closer ties to industry and national and international collaborators to meet those goals.
Approved Disease Team projects:
|Grant number||Investigator||Institution||Intl. Collaborator||Total CIRM Funding|
|DR1-01421||Karen Aboody||City of Hope National Medical Center||$18,015,429|
|City of Hope National Medical Center|
|Larry Couture||City of Hope National Medical Center|
|The group proposes to treat brain tumors using neural stem cells that are genetically modified to carry a tumor-killing drug.|
|DR1-01423||Emmanuel Baetge||Novocell, Inc||$19,999,937|
|University of California, San Francisco|
|The group proposes to treat people with type 1 diabetes by implanting insulin-producing cells generated from human embryonic stem cells.|
|DR1-01426||Mitchel Berger||University of California, San Francisco||$19,162,435|
|Ludwig Institute for Cancer Research|
|Evan Snyder||Burnham Institute for Medical Research|
|The group proposes to treat brain tumors using neural stem cells that are genetically modified to carry a tumor-killing drug.|
|DR1-01430||Dennis Carson||University of California, San Diego||Canada||$19,999,826|
|University of California, San Diego|
|University Health Network|
|The group intends to develop six drugs – three monoclonal antibodies and three small molecules – to destroy leukemia stem cells.|
|DR1-01431||Irvin Chen||University of California, Los Angeles||$19,999,580|
|This group proposes to treat HIV/AIDS using an RNA interference approach to modify the patient’s blood-forming stem celis. When transplanted back, those cells will produce T cells that are resistant to HIV infection.|
|DR1-01444||Mark Humayun||University of Southern California||MRC||$15,904,916|
|University of Southern California|
|Dennis Clegg||University of California, Santa Barbara|
|University College London-Institute of Ophthalmology|
|The group intends to treat macular degeneration using transplant retinal cells derived from human embryonic stem cells.|
|DR1-01452||Donald Kohn||University of California, Los Angeles||$9,212,365|
|Children’s Hospital of Los Angeles|
|Victor Marder||University of California, Los Angeles|
|The group proposes to treat sickle cells disease using a gene therapy approach to modify the patient’s blood-forming stem cell so that they produce normal red blood cells.|
|DR1-01454||Alfred Lane||Stanford University||$11,709,574|
|Marius Wernig||Stanford University|
|The group proposes to treat the skin disease epidermolysis bullosa using genetically modified iPS cells created from the patient’s own skin cells.|
|DR1-01461||Eduardo Marban||Cedars-Sinai Medical Center||$5,560,232|
|The group intends to repair heart tissue damaged by heart attack using stem cells taken from the patient’s own heart.|
|DR1-01471||Samuel Pfaff||The Salk Institute for Biological Studies||$15,644,881|
|University of California, San Diego|
|Don Cleveland||Ludwig Institute for Cancer Research|
|The group intends to treat people with Amyotrophic lateral sclerosis by implanting precursor astrocyte cells derived from human embryonic stem cells.|
|DR1-01477||Dennis Slamon||University of California, Los Angeles||Canada||$19,979,660|
|Michael Press||University of Southern California|
Tak Wah Mak
|University Health Network|
|The group proposes to develop drugs that destroy the cancer stem cells in solid tumors.|
|DR1-01480||Gary Steinberg||Stanford University||$20,000,000|
|University of California, Los Angeles|
|The group intends to treat stroke using implanted neural stem cells derived from human embryonic stem cells.|
|DR1-01485||Irving Weissman||Stanford University||MRC||$19,999,996|
|Beverly Mitchell||Stanford University|
|Weatherall Institute of Molecular Medicine, Oxford University|
|The group intends to generate a monoclonal antibody that destroys leukemia stem cells.|
|DR1-01490||John Zaia||City of Hope National Medical Center||$14,583,187|
|University of Southern California|
|David DiGiusto||Beckman Research Institute of City of Hope|
|This group proposes to treat HIV/AiDS using a gene therapy approach to modify the patient’s blood-forming stem celis. When transplanted back, those cells will produce T cells that are resistant to HIV infection.|