Lofty promises, limited results After 14 years and $3 billion, has California's bet on stem cells paid off? By Erin Allday and Joaquin Palomino

It was an extraordinary political proposal: Approve a $3 billion bond measure to fund the cutting-edge science of stem cell therapy, and soon some of the world’s cruelest diseases and most disabling injuries could be eradicated.

The 2004 measure was Proposition 71, the California Stem Cell Research and Cures Initiative. The campaign to pass it was led by a Palo Alto real estate developer whose son suffered from an incurable illness that he believed stem cells, the keystones of human biology, could heal. Other supporters included preeminent scientists, Hollywood celebrities, business leaders and elite investors.

The Miracle Cell This series explores the hope and reality of the revolutionary science of stem cell therapy. It focuses on what has transpired since 2004, when California voters approved a $3 billion bond measure to fund stem cell research with the promise that it soon would produce new treatments for incurable diseases. In four parts, it follows the stories of patients desperately seeking remedies; probes the for-profit clinics where unproven and unregulated treatments are being offered; takes you into the labs and hospital rooms where scientists are testing new therapies; and provides a comprehensive accounting of what California’s multibillion-dollar bet on stem cells has achieved.

The need was urgent, they said. Federal restrictions had recently been imposed on funding research involving human embryonic stem cells, then the most auspicious field of study.

Among the campaign’s promises: Nearly half of all families in California could benefit from stem cell treatments Prop. 71 would help create. One study it commissioned found that new, life-changing therapies could emerge in just a few years. And Prop. 71 would pay off financially, the campaign claimed, creating thousands of jobs and potentially returning the state's investment more than seven times over.

"How many chances in a lifetime do you have to impact human suffering in a really fundamental way, including possibly even in your own family?" Robert Klein, the campaign leader, would say shortly after the vote.

In November 2004, Prop. 71 passed with nearly 60 percent approval. It created the California Institute for Regenerative Medicine, or CIRM, an agency tasked with administering the $3 billion and making the campaign’s lofty visions a reality.

Fourteen years later, the money voters approved is nearly gone, and supporters of CIRM and the research it funds are preparing to ask the public for another $5 billion in 2020. This time, taxpayers will want to know: Has California’s initial bet on stem cell science paid off?

Over the past several months, The Chronicle conducted an extensive analysis of CIRM’s spending, reviewing the nearly 1,000 grants the agency has made, tracking how the money has been spent, and gauging whether the promises have been realized.

It’s not a question that can be answered simply. Science often can’t be measured in quantifiable outcomes. Failures aren’t just common, they’re necessary — it’s impossible to expect every dollar invested in research to lead down a traceable path toward success.

CIRM can take credit for some notable progress.

It has helped make California a global leader in the field that’s come to be known as regenerative medicine. Anywhere significant stem cell research is taking place in the state, it almost surely has received support from CIRM.

About the science Children with severe combined immunodeficiency, also known as “bubble baby” disease, are born with almost no immune system. The treatment developed at UCLA is a gene therapy. Doctors remove stem cells from the child’s bone marrow, add a normal copy of the gene that’s causing the disease, then reinfuse the stem cells back into the child. The repaired stem cells build a healthy new immune system.

About the science The research involves stem cells culled from donated bone marrow tissue. The stem cells are genetically engineered in a lab, then transplanted directly into patients’ brains. The genetic engineering causes the stem cells to behave in a way that reverses damage done to native neural cells in the brain — scientists still aren’t clear exactly how. In early clinical trials, several patients have reported significant recovery, including regaining the use of arms, legs and speech.

About the science The procedure to treat alpha thalassemia major — a disease that is often fatal before or shortly after birth — involves transplanting stem cells from the mother into the baby’s bone marrow while it’s in the womb, during the second trimester. The hope is that the mother’s healthy stem cells will knock out the unhealthy cells in the growing fetus and reverse the disease. So far, one baby — a girl born at UCSF Medical Center at Mission Bay in February — has been treated.

Editor's note: Click on highlighted text to learn more about CIRM-funded science.

At UCLA, doctors are using stem cells to cure a rare immune deficiency disease that kills children. At Stanford, early studies show that stem cells deposited deep into the brain could restore movement and speech to people devastated by stroke. At UCSF, a team is beginning human trials for a fatal genetic blood disease that involves transplanting stem cells into a fetus still in the uterus.

But as thrilling as such advances are, they fall far short of what Prop. 71’s promoters promised.

Not a single federally approved therapy has resulted from CIRM-funded science. The predicted financial windfall has not materialized. The bulk of CIRM grants have gone to basic research, training programs and building new laboratories, not to clinical trials testing the kinds of potential cures and therapies the billions of dollars were supposed to deliver.

Over that same time, many people suffering from incurable diseases have become impatient waiting for scientists to produce the miracle treatments the Prop. 71 campaign said were within reach.

Instead, a thriving, for-profit industry of clinics offering dubious stem cell therapies based on half-baked science has sprung up, defying attempts at government regulation and requests from scientists to proceed cautiously.

Now, as CIRM supporters prepare to approach voters again, some say its achievements shouldn’t be measured only against the claims made by the campaign that created it.

“What was promised was not deliverable,” said longtime CIRM board member Jeff Sheehy, a former San Francisco supervisor. “However, I would distinguish the promises from the impact and value. We have developed a regenerative medicine juggernaut.”

Klein, though, is unapologetic about the campaign he led. Indeed, as he lines up advocates and testimonials for the coming campaign, his message is familiar: Fund this research and we will save lives. Slow it down and the consequences will be grave.

“Do you want your son to die? Are you going to wait?” Klein asked recently. “Is that the price you are prepared to pay?”

In his airy, sunlit lab at San Francisco’s Gladstone Institutes, cardiologist Deepak Srivastava has used skin cells to produce heart cells. As they pulse in a petri dish, their steady, calming beat feels familiar, even viewed through the lens of a microscope.

About the science Deepak Srivastava has developed techniques for turning fibroblasts — a type of connective cell located throughout the body — directly into heart cells. His group has converted fibroblasts in the hearts of mice and pigs into muscle cells, helping repair the heart after damage. It could lead to a therapy allowing doctors to turn fibroblasts in human hearts into cardiac cells, replacing cells damaged by a heart attack.

Someday, he hopes, the work of his team at Gladstone’s Roddenberry Stem Cell Center will lead to a therapy that can reverse the effects of a heart attack.

“We got this far purely because of CIRM,” said Srivastava, the center’s director.

The dream of exploiting the human body's remarkable ability to heal itself — to grow skin and bone, to replace muscle lost to wasting or disease, to undo systemic damage caused by infection — has long captivated medical scientists. In the late 1800s, they began to suspect that specific cells in the body were responsible for this repair and regeneration work.

A century later, in 1981, UCSF scientist Gail Martin gave the most powerful of these cells a name: embryonic stem cells.

It wasn’t until 1998 that the first human embryonic stem cells were isolated and replicated in a lab. These cells are uniquely potent, responsible for building every part of a human body. As an embryo matures, it rapidly replicates, transforming into bone cells and muscle cells, brain cells and heart cells.

Some doctors believed if they could harness stem cells, they could use them to treat all but the most disastrous threats to the body, perhaps even reverse the natural effects of aging.

The process of isolating them, though, involved destroying days-old embryos. Religious and antiabortion groups decried the science as unethical. In 2001, President George W. Bush instituted far-reaching limitations on federal grants for embryonic stem cell research.

In California, advocates for regenerative medicine sought a way around the funding restrictions. Their solution: Prop. 71, which would generate $3 billion in general obligation bonds, the type more often used for infrastructure projects like highways or dams. Including principal and interest, the total cost to taxpayers would be roughly $6 billion.

State-funded scientific research on that scale had never been attempted and, despite the campaign’s pitch, there was no guaranteed payoff. The state Legislative Analyst's Office offered a cautious assessment: The potential financial benefits were unknown.

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Klein, then a major Silicon Valley developer, helped conceive, bankroll and write Prop. 71. For him, the effort was personal. His son, Jordan, had recently been diagnosed with Type 1 diabetes, and Klein had become a ferocious advocate for people with brutal conditions and little hope.

More than 20 Nobel Prize laureates backed the proposal. So did Hollywood celebrities such as Michael J. Fox and Brad Pitt. Million-dollar donations came from the founders of eBay and the owner of the Cleveland Cavaliers basketball team.

About the science In Parkinson’s disease, certain brain cells are killed. Transplanting that type of cell into patients may improve their symptoms dramatically. Such a therapy would require a large supply of those brain cells, which can be made from embryonic and induced-pluripotent stem cells. Scientists at the Buck Institute in Novato have studied ways to streamline manufacturing and produce more consistent results, which could speed up study of the brain cells for Parkinson’s.

Radio and television ads featured gut-wrenching appeals from people with incurable diseases. Patient advocate Joan Samuelson, later appointed to CIRM’s board, said in one ad that Prop. 71 “will rescue me, and a million people with Parkinson’s disease.”

In another, “Superman” actor Christopher Reeve, paralyzed from the neck down after a horseback riding accident, said “stem cells have already cured paralysis of animals” and called them the “future of medicine.” Dependent on a ventilator attached to his trachea, he struggled to breathe and to speak in the ad. He died before the spot aired.

A TV ad for the Prop. 71 campaign featured Christopher Reeve, who died a few weeks before it aired.

On Nov. 2, 2004, Prop. 71 passed by 59 percent to 41 percent. It would take years, though, for the unprecedented experiment voters had approved to fully launch.

Almost immediately, critics filed lawsuits. CIRM, the new stem cell institute, lacked public accountability, they said. While technically it was a state agency, the measure gave the Legislature little direct oversight of it. The legal challenges eventually were dismissed, but they slowed funding for nearly two years.

Meanwhile, the confident claims of the campaign were being tempered with more modest expectations. A year after moving into its San Francisco headquarters, CIRM would unveil a 10-year plan dramatically scaling back the pledges made by Prop. 71.

The field of embryonic stem cell research was still young, the report warned. The road to marketing new therapies would be long and expensive. Most research never reaches human clinical trials, it explained, and most of those trials fail. Potential treatments for just a handful of diseases might be tested, and it was doubtful that a single approved therapy would be developed from the state’s investment.

“The whole tenor of the campaign, what was said on television ads that flooded the state and by Bob Klein and his lobbying group, was that if California would fund this work, there would be cures,” said Marcy Darnovsky, executive director of the Center for Genetics and Society in Berkeley. “People that were saying that must have known you can’t schedule medical breakthroughs. Those hopes were just that, hopes, and completely speculative.”

But as CIRM ramped up, The Chronicle’s review shows, it began doling out grants at a furious pace, averaging more than $7 million a week in 2008, its first year of full-fledged operation. To date, CIRM has spent or committed more than 90 percent of its $3 billion allowance.

The grants can be broadly divided into four categories: basic science and training; infrastructure; translational and preclinical, which is the work that goes toward moving laboratory science into human studies; and clinical trials.

The Chronicle reviewed CIRM grants through May 2018, tracking who received money and how it was spent.

Bay Area institutions have been especially well-funded, with more than one-fifth of the bond money funneled to Stanford, UCSF, UC Berkeley and the Gladstone Institutes. Stanford, the biggest beneficiary, has received $360 million in grants. CIRM’s funding of Stanford, a private institution supported by a hefty endowment, has at times been sharply criticized.

Following the Money In 2004, California voters approved Proposition 71, which set aside $3 billion in bond money toward funding stem cell research. Since then, the California Institute for Regenerative Medicine has spent or earmarked $2.75 billion. Hover over the chart or colored text below. Click on the chart below. Grants have been awarded in these main categories: basic research, education, infrastructure, preclinical/translational – which is focused on shifting basic science work into human trials – and clinical trials. The bulk of the money has gone to public universities and colleges. Private universities like Stanford have also won big. The remaining grant money has gone to research institutes and for-profit companies. Emma O'Neill / The Chronicle Source: California Institute for Regenerative Medicine Note: Recipient list is not complete. All data are through May 2018. Roughly $40 million in CIRM loans was not included. Grants to research institutes include some small conferences. * Includes Sanford Consortium and Sanford-Burnham ** Quintiles now called IQVIA.

Nearly 40 percent of the total bond money, more than $1.1 billion, has gone into training programs and basic research — work largely aimed at improving scientists’ understanding of stem cells and how they might be best used in medicine.

About the science UCLA scientists have found a way to spur growth of a type of immune cell that promotes “tolerance.” These T-cells prevent the immune system from attacking its own tissue, as in autoimmune diseases, or donated tissue from transplants. The UCLA team is developing techniques for enhancing T-cell growth from bone marrow stem cells.

About the science Christine Brown at the City of Hope in Duarte (Los Angeles County) is studying malignant glioma, aggressive brain tumors that have a high likelihood of recurrence because stem cells in the tumors are often resistant to traditional cancer therapies. Her team is seeking ways to trigger a patient’s own immune system to attack the cancer stem cells, using a type of immune cell called a CAR T-cell that’s recently been used to fight blood cancers. So far, patients treated with a therapy developed from this research have shown encouraging results; one patient’s tumors regressed completely.

About the science Scientists build so-called organoids by turning adult cells — like skin or blood cells — into stem cells and then into cells from whatever organ they want to study. These organoids allow them to study hard-to-reach places like the brain, and to create models of brains affected by disease. Earlier this year, A team of scientists from the Salk Institute in La Jolla (San Diego County) this year transplanted a brain organoid into a mouse, which may improve their ability to study brain activity in a natural environment.

These basic biology studies have helped scientists develop techniques that could prevent immune rejection from an organ transplant. They discovered weak points in cancer stem cells that might become new targets for drug therapies. In addition to Srivistava’s beating heart cells, scientists have used stem cells to build mini-organs, including “brains” in petri dishes for testing drug therapies and learning more about diseases like Alzheimer’s.

CIRM’s focus, meanwhile, has expanded beyond embryonic stem cells. It has funded research involving adult stem cells, which exist in pockets throughout the body and are cheaper and less controversial than embryonic stem cells. It’s also invested in induced-pluripotent stem cells, first developed in 2006. Produced from other types of cells, they look and act like embryonic stem cells.

Induced-pluripotent stem cells, developed in 2006 by a Japanese scientist, were a potential game changer for stem cell research. Embryonic stem cells are defined by their ability to turn into any other kind of cell — a trait known as pluripotency. Shinya Yamanaka, who is affiliated with the Gladstone Institutes in San Francisco, found that by applying certain genetic triggers — later, they were called “Yamanaka factors” — to an adult cell he could make that cell pluripotent. Yamanaka won the Nobel Prize in 2012 for his discovery. Induced-pluripotent stem (IPS) cells behave like embryonic stem cells. They can be further developed to become other cell types, such as heart and brain cells. So in theory, scientists could use cells that we have a rich supply of — like skin and blood cells — to replace cells in the brain or heart or other organs that are not easily restored. Many scientists believed at the time of Yamanaka’s discovery that IPS cells would solve the ethical dilemma of obtaining embryonic stem cells from human embryos. That’s taken longer than expected, but scientists are starting to develop therapies using IPS cells instead of embryonic stem cells. In the United States, IPS cells are used mostly for disease modeling. Scientists take cells from people with certain genetically linked diseases, create IPS cells, then build models in culture dishes to study the illness. For example, scientists can create clusters of brain cells that are affected by Alzheimer’s disease, then test drugs on those brain cells to see if any will affect the course of the illness. There are not yet any clinical trials with IPS cells in the United States. Japan has two clinical trials using the cells, one involving a treatment for macular degeneration and another for Parkinson’s disease. Both are in early tests for safety.

CIRM-funded researchers have published more than 330 scholarly articles in four of the most respected stem cell and academic journals. Each represents a new discovery in the field and has enabled the work California has funded to reach scientists around the world.

CIRM’s investments in infrastructure have amounted to $482 million — 16 percent of the bond money. Most of that went toward building a dozen stem cell research centers.

UCSF received a $35 million grant to help raise a glass-and-metal structure on the hillside overlooking its Parnassus campus. The independent Buck Institute for Research on Aging received $20 million toward a sleek white building on its Novato grounds. Stanford University won the largest single grant: $43.6 million toward a four-story structure at the edge of its medical school campus built around a glass-walled atrium.

About $388 million has gone toward preclinical and translational research: studies that take science out of the lab and try to apply it to humans. This phase of research, seldom backed by the federal government, can be particularly challenging. A therapy that looks promising when tested on a cluster of cells in a laboratory-controlled environment often fails when given to more complex organisms.

About the science Calimmune Inc., based in Tucson, completed an early-phase clinical trial testing its gene therapy on 12 people with HIV. The treatment involves genetically modifying patients’ own stem cells, drawn from their bone marrow, and T-cells so that they produce immune cells that are protected from HIV. The hope is that once those gene-modified cells are returned to patients, they could rebuild the immune system and fend off the virus, potentially leading to a cure.

About the science Peripheral artery disease occurs when the arteries that supply blood to the legs become narrow or blocked entirely. The gel, taken from pig skeletal muscles, contains structural materials that form a scaffold when they’re injected into a subject. That scaffold lures stem cells and encourages growth of muscles and blood vessels. In animal studies, the gel increased the diameter of large blood vessels. The research, led by bioengineer Karen Christman, was done at UC San Diego.

The preclinical studies funded so far reflect the immense possibilities stem cells offer: Scientists have examined a gene-modifying technique to try to treat HIV. They’re studying small molecule drugs that could destroy leukemia stem cells. They’re developing a gel derived from pig muscles that could stave off amputations among people with a disease that weakens blood circulation.

The research has helped CIRM-backed scientists license 107 invention disclosures. Some of the studies have paved the way for clinical trials, while others have hit dead ends.

About the science Henry Klassen uses fetal-derived retinal progenitor cells — immature cells that form the retina, including the rods and cones that are responsible for vision and that are destroyed in retinitis pigmentosa. The cells are injected directly into patients’ eyes, where they deliver factors that preserve and enhance visual function. Klassen’s team has finished a clinical trial testing the safety of the cells; a second trial is assessing efficacy.

CIRM funding helped push UC Irvine scientist Henry Klassen’s work from lab studies to clinical trials testing a stem cell therapy for a rare form of blindness. His research, which has shown success, has largely been carried out in a building at UC Irvine partly underwritten by CIRM.

“The whole reason I’m here in California is because of CIRM,” said Klassen, who had been working in Singapore and took a job at Irvine shortly after Prop. 71 passed. “This consistent source of funding has been critical as we go from the bench to the bedside.”

Still, critics and supporters alike say those who pushed Prop. 71 significantly oversold the short-term medical and financial prospects of stem cells.

No federally approved treatments have been produced. And without marketable therapies, the public is still far from reaping the up to $91 billion in health care savings by 2040 the campaign predicted.

CIRM has funded nearly 50 clinical trials, but just four have been completed, meaning scientists enrolled all the patients they said they would and finished compiling data. One of those trials was an observational study that tested no new therapy. The others involved treatments that are still years, at best, from reaching the market.

California’s stem cell experiment: ORIGINS In 2004, California voters passed Proposition 71. It authorized the sale of $3 billion in bonds for stem cell research and created the California Institute for Regenerative Medicine, or CIRM, to administer grants using the bond money. Legal challenges slowed down funding for nearly two years. BUILDING THE BASICS The earliest grants went mostly toward building labs and funding basic science — research that does not directly help patients but can lead to tools and therapies that can be tested in clinical trials someday. In 2007 alone, nearly $70 million went to infrastructure and more than $157 million to basic science. In 2008, CIRM made its largest single grant: $43.6 million to Stanford University for the Lokey Stem Cell Research Building. CIRM issued the bulk of its basic science grants between 2007 and 2012. CIRM’s investments in basic science continue, but have decreased in recent years. Through May 2018, no basic science grants were awarded. PRECLINICAL CIRM came under mounting public pressure to fund research that would produce stem cell therapies or cures. The first step was funding preclinical work, which is research that moves basic science toward human trials. Through 2011, CIRM directed roughly $175 million to preclinical work. Some years, no money went toward preclinical work. By 2012, CIRM began shifting resources toward preclinical and clinical research. CIRM granted more than $125 million for preclinical research in 2016, 2017 and 2018. CLINICAL Since 2012, CIRM has directed more than $500 million to clinical work, mostly on safety trials. It has funded 49 clinical trials, targeting conditions such as spinal cord injury, blindness, stroke and Type 1 diabetes. In the first five months of 2018, CIRM exclusively funded clinical and preclinical research, spending nearly $70 million on clinical trials and $18.6 million on preclinical studies. FUTURE In early 2016, CIRM committed to funding 50 new clinical trials by 2020. The agency is on track to meet that goal, but some believe its push to fund more clinical trials is premature. Six CIRM-funded clinical studies are phase 3 trials, which test whether a therapy is effective among large groups of patients, often the last step before FDA approval. But two of the trials were terminated or suspended before they were completed. Five CIRM-funded trials — for spinal cord injury; a degenerative eye condition that causes blindness; renal failure that requires frequent dialysis; an inherited form of muscular dystrophy; and angina, or chest pain caused by reduced blood flow to the heart — have been fast-tracked by the FDA. No treatment developed from CIRM-funded research has won FDA approval yet.

The state, once told to expect as much as $1.1 billion in royalties from CIRM-backed discoveries within 35 years, so far has received just a tiny fraction of that amount: a single payment of $190,000 from the City of Hope medical research center in Los Angeles County.

Other economic benefits, such as tax revenues and new jobs, have been measured only a handful of times. The most recent study, which CIRM commissioned using public funds and published in 2012, showed the state investment had helped create tens of thousands of jobs and generate hundreds of millions in tax revenue.

The aim of the report, however, was to aggressively support the goals and initiatives of CIRM, according to the California Stem Cell Report, a blog that has diligently tracked the institute.

CIRM and its 29-person governing board, meanwhile, have been a frequent target of attack.

State lawmakers have introduced multiple bills aimed at making the institute more accountable to the public and at ensuring that all taxpayers, not just biotech companies and universities, would benefit from the public investments.

Almost every effort has failed, in part due to the unusually restrictive language of Prop. 71: Any change in CIRM’s structure needs a voter initiative or a 70 percent vote in both houses of the Legislature and the governor’s approval.

The proposition also specified the precise makeup of the agency’s governing board, placing representatives of many of the institutions that CIRM funds to oversee its grants. Having such built-in conflicts of interest without the oversight expected of a public agency has undermined CIRM’s legitimacy, critics say. They have likened it to an insiders’ club that enriches its own members.

“These guys got away with an incredible amount of personal enrichment,” said state Sen. John Moorlach, R-Irvine, a longtime critic of CIRM. “And all they gave us was debt.”

CIRM leaders say they have strong protections to ensure that personal interests don’t influence funding decisions: Board members don’t discuss or vote on proposals they have a financial stake in, and an out-of-state review panel has a major say in which projects are funded.

Multiple audits, however, have found the sheer volume of recusals troubling.

Records obtained by The Chronicle showed that board members abstained from voting on grants roughly 1,770 times since 2006 due to reported financial conflicts. Tens of thousands of additional recusals were triggered by a CIRM policy that bars certain members from weighing in on any application.

In some cases, nearly half of the board was unable to vote on major and controversial proposals due to conflicts of interest.

One board member, UC Regent Sherry Lansing, a former film studio executive, has recused herself from more than 400 grant discussions because of a tangle of conflicts, most related to the universities she oversees. Lansing’s role is to advocate for cancer patients.

A pivotal Institute of Medicine review in 2012 found that such widespread conflicts had caused some to “question the integrity and independence” of CIRM, and it recommended sweeping reforms. Many of the suggestions were not enacted, although CIRM did make some significant changes shortly after the report published.

Klein, CIRM’s board chairman during its first seven years, has been a divisive figure. Despite his role at CIRM, he continued to run a patient advocacy group that regularly dismissed concerns about the agency and attacked many people, including legislators, who challenged it. A 2009 Little Hoover Commission report called him “a lightning rod for calls for more accountability.” There were multiple demands for his resignation.

“There’s a reason you have checks and balances, transparency and accountability when you use that much in public funds, and unfortunately none of that was in place,” said former state Sen. Deborah Ortiz, who strongly supported Prop. 71, then became a CIRM critic. “You can't go to the voters and say, ‘Let’s use $3 billion in state funds,’ then say, ‘We don’t want the terrible government to bother us.’ ”

Even some of CIRM’s most ardent supporters — patients and patient advocates who stand to benefit most directly from stem cell therapies — have become critical. Their chief complaint: The science is taking too long, and they’re running out of time.

At the Gladstone Institutes’ Mission Bay campus last fall, CIRM held a public meeting to update patients about the research going on throughout California.

CIRM representatives and scientists told the story of a mother who had her vision partially restored after enrolling in Klassen’s trial at UC Irvine. They talked about an East Bay teenager, paralyzed the day before graduating high school, who regained some movement after receiving a stem cell transplant.

The $3 billion bond, they said, had made these achievements possible.

“What you will see over the next decade,” Srivastava of the Gladstone Institutes told the crowd, “are a series of breakthroughs for many diseases based on that investment.”

Not everyone shared his enthusiasm.

“I’ve met hundreds, thousands of people with spinal cord injuries,” Franklin Elieh, a quadriplegic man and patient advocate, said at the same meeting. “Millions are suffering needlessly and endlessly. Billions (of dollars) are being spent needlessly and endlessly. What can be done to really accelerate this?”

Elieh, like many people living with incurable diseases or conditions, is disillusioned with the dearth of clinical trials CIRM has backed.

Clinical trials are the goal of laboratory medical science. They are the moment that a possible treatment, studied only in a test tube or a dish or an animal, finally is tested on a human subject.

The first two trial phases primarily test safety: Does this treatment, when given to a human being at an effective dose, cause intolerable side effects? Phase 3 trials are typically the first to tell scientists how well a therapy works in large groups of patients, if it works at all. They are often the last step before scientists — usually working with a for-profit company that has financed the increasingly expensive research — seek FDA approval.

About 900 patients have been involved in the 49 clinical trials CIRM has backed so far, The Chronicle’s review shows. Nearly a fifth of CIRM’s funds, about $530 million, has gone to support the trials. Most of those grants were awarded in the past three years, part of a deliberate effort by the agency to direct more money toward testing treatments.

“Every single project we have is spectacular, and just a couple of years ago may have been considered science fiction,” CIRM President Maria Millan told a state legislative committee in August as she outlined many of the clinical trials the agency has funded.

About the science North Carolina company Humacyte takes muscle cells from organ donors and induces them to form hollow tubes about the width of a pinky finger. First, the cells cluster on biodegradable, tube-shaped scaffolds until they hold the shape on their own. Scientists then wash off the cells, leaving behind tubes made of cellular “glue.” The tubes are transplanted into patients’ arms. A patient’s own stem cells are drawn to the tube and form a blood vessel around it. That vessel can be used for dialysis in place of a shunt, which can require surgical replacement or adjustment as often as once a year.

Only six of the clinical trials, though, have been phase 3 studies. Of those, two were terminated or suspended, three are still recruiting patients, and one — for a bioengineered blood vessel that can be used in dialysis — is under way.

Meanwhile, the National Institutes of Health, the primary federal funding agency for medical research, has far outpaced CIRM in supporting clinical trials in stem cell research. A 2017 analysis by STAT, a science and health news publication, found that, dollar for dollar, the NIH funded 3 1/2 times as many clinical trials as CIRM from 2006 to 2016.

In 2009, President Barack Obama lifted most of the restrictions on federal funding of embryonic stem cell research, but for both agencies, trials using those cells remain rare.

“When we voted for Prop. 71 we wanted clinical trials, we didn’t want basic research,” said Judy Roberson, a longtime CIRM supporter who has lost five family members, including her husband, to Huntington’s disease. Roberson has 17 other relatives who are also at high risk of developing the hereditary neurological disorder, which slowly erodes a person’s ability to walk and talk.

“Our loved ones are going to die. They’re sitting on time bombs,” she said. “You could do basic research for 100 years, but you’re never going to learn everything. So just get in there and try something.”

But accelerating the push of basic science toward human trials is not without its critics. The International Society for Stem Cell Research — the largest body of scientists looking at policy and politics in regenerative medicine — has cautioned against that approach. Many scientists say that, in general, it’s too early to be experimenting on people, particularly with embryonic and induced-pluripotent stem cells, which may cause tumors.

Gene therapy, a field related to stem cells, underwent more than 30 years of grueling research and repeated setbacks before establishing its first commercial successes in 2017: two cancer treatments approved by the FDA.

Embryonic stem cells were isolated for the first time just two decades ago. Induced-pluripotent stem cells were made only 12 years ago. Adult stem cells — the cells responsible for regular repair and upkeep — have been used in bone marrow transplants for more than 50 years, but their application beyond that started to be deeply studied only in the 1980s.

About the science Arnold Kriegstein studies a specific kind of brain cell found in human embryos that can control brain cells that become overactive in people with epilepsy or Parkinson’s disease. The overactive cells cause classic symptoms such as seizures in epilepsy or tremors, rigidity and problems with walking and balance in Parkinson’s. Kriegstein’s team is part of a broader effort looking for ways to generate large numbers of the controller brain cells from stem cells and safely transplant them into the brain.

The science simply isn’t there yet, said Arnold Kriegstein, head of UCSF’s stem cell center, who has received $2.5 million from CIRM for basic research.

“CIRM touts 50 or so projects moving toward the clinic, and many of them will likely fail,” Kriegstein said. “It might be more prudent to spend dollars solving basic research problems, where a relatively modest investment can have a huge impact.”

Some suggest that CIRM’s recent aggressive support for clinical trials is directly tied to its plan to return to voters for more funding. The fact that its work is supported by taxpayers increases the urgency to produce results, said Timothy Caulfield, a Canadian law professor at the University of Alberta who closely follows CIRM.

“That creates a lot of pressure to frame the work in terms of near-future miracles, and that will almost always fail,” Caulfield said. “True medical breakthroughs with broad application are incredibly rare.”

To patients desperate for cures, CIRM leaders say stay hopeful. The work may be taking longer than promised, but it will pay off in the end. And the state has too much invested now to give up. Such hope, though, isn’t easy to come by for those beginning to realize that any therapies to help them probably will arrive too late.

“We see how slow progress is, and we know a lot of people are never going to be candidates for a treatment,” said Elieh, who is co-founder of the Northern California Spinal Cord Injury Foundation, a nonprofit patient support group.

Elieh, 54, was injured in a diving accident in 1989, shattering his vertebrae and damaging his spinal cord so badly that he lost movement in his legs and upper body. In the years afterward, he enrolled in clinical trials and costly rehab programs, but none helped.

During the Prop. 71 campaign, Elieh watched celebrities talk about the miraculous ability of stem cells to regenerate tissue. He saw videos of paralyzed rats that could walk again after receiving an injection of stem cells. Clinical trials, scientists said, were just years away.

“Everyone you talked with thought, ‘Wow, we’re going to put $3 billion into this,’ ” Elieh said. “It was really creating hope. And, unfortunately for me, false hope.”

Over the past decade CIRM has funded two clinical trials testing the same treatment for spinal cord injuries. The therapy, though, applies only to people newly injured, not the hundreds of thousands of men and women like Elieh who have been paralyzed for years.

So far, the therapy has proven safe. A handful of patients in the second trial regained some movement, though it’s too soon to say whether stem cells are the reason. While CIRM supporters are keen to hold up that trial as an example of the stunning potential of stem cell therapies, Elieh and many of his peers are more cautious.

“We’ve still barely taken the first step, and we have no idea when the second step will land,” Elieh said. “We all had a lot of hope back then, and we’ve just kept hoping.”

Seated on a stage before 50 people in a town-hall-style meeting in Mill Valley, Art Torres had one word to describe the results of the CIRM-funded trial for spinal cord injuries: “Miraculous.”

Torres, former state senator and long-time member of the CIRM board, was enthusiastic in a way that would have made the more cautious scientists running the trial cringe. But CIRM needs a home run.

The looming end of its funding — and the need to ask voters for billions more — presents an existential moment.

Since 2004, the political and scientific climate has changed significantly. Federal funding for embryonic stem cell research is no longer tied up, and many voters are savvier about the limitations of regenerative medicine. The scientists backed by CIRM, meanwhile, face unconventional competition from an unexpected source: a vibrant consumer-clinic industry that’s marketing unproven therapies to those tired of waiting for cures.

Prop. 71’s most tangible achievements — cutting-edge academic buildings, discoveries in petri dishes, advances in lab rats, pioneering trials in human subjects — aren’t necessarily going to resonate with voters. What will are visible triumphs in real people. Those successes are what CIRM’s most ardent supporters are rallying around.

On the cover of the agency’s 2017 annual report was a wide-eyed infant named Ronnie. He was cured of an immune deficiency disease called SCID, or “bubble-baby disease.” Children who have the condition typically live in isolation to protect them from fatal infections.

CIRM has helped fund four trials, all at different institutions, testing stem cell therapies for SCID. Ronnie was treated at UCSF using a treatment developed at St. Jude Children's Research Hospital in Tennessee. A therapy out of UCLA, which has been in clinical trials since 1993, could win FDA approval — a first for CIRM-backed research — in a year or two, say the scientists who developed the treatment. In all, 40 babies have been treated with the UCLA therapy.

And there’s Rosie Barrero.

In a video posted on CIRM’s website, Barrero sits in a sunny room at the agency’s headquarters, now in Oakland, Lake Merritt glittering behind her. She’s earnest as she talks about retinitis pigmentosa, the disease that has slowly blinded her.

Barrero was treated in 2016 in Henry Klassen’s trial for patients with RP. Within months, she could pick out colors and shapes she hadn’t been able to see for years. She could tell her daughters apart. She has regained about “a pinhole” of sight, but that she’s had any improvement at all, she said, is amazing: It means that the therapy works.

“We’re definitely hoping that this work continues to get funded,” Barrero said in an interview. “It’s incredibly important, to all of us.”

If a new bond isn’t approved in 2020, said CIRM President Millan, it could devastate stem cell research in California. Private industry is still reluctant to back research that has yet to produce a treatment, let alone show it can be profitable.

And so, CIRM proponents are turning again to Robert Klein, who plans to lead the 2020 campaign for more research dollars.

In Klein’s downtown Palo Alto office, a series of photos — colorful, fantastical close-ups of stem cells studied by CIRM scientists — hangs above his desk. Once they’d hung in CIRM’s offices. Today they reflect the deep connection he’s retained with the agency, despite not having an official role since stepping down as board chairman seven years ago amid a flurry of criticism.

Late last year, Klein addressed the CIRM board at a meeting about the fate of the agency. According to polls he had paid for — the full results of which he declined to share — 70 percent of voters would support another stem cell funding proposition. No other options for future financing — not private fundraising, not legislative efforts — would work, he said.

About the science ViaCyte Inc. in San Diego is conducting clinical trials of an implant that delivers immature islets to people with Type 1 diabetes. Islets contain the insulin-producing cells in the body; in people with Type 1 diabetes, the immune system destroys these cells. Transplants from donor islets can be effective in treating Type 1 diabetes but there are limited sources of those cells. Islets made from stem cells could overcome that supply problem and lead to a therapy that could effectively cure diabetes in some people.

It was his son Jordan’s battle with Type 1 diabetes that drove Klein into patient advocacy and stem cell research. But the therapies that Klein believed were imminent did not arrive in time to save Jordan. Two years ago, at age 26, he died from complications related to the disease.

The loss seems to have cemented Klein’s resolve.

“We couldn't get there fast enough for Jordan,” Klein said. “We have to get there for everyone else.”

Klein rejects the notion that expectations for CIRM were overhyped or voters misled in the 2004 campaign. If cures aren’t yet at hand, they’re surely years closer than they would be without CIRM, he said, and people already are benefitting from research paid for by Prop. 71.

During an interview in his office, Klein played a brief video of a young man who is part of the spinal cord injury trial CIRM has helped fund. Made quadriplegic after a devastating car accident, the man is shown in the video lifting weights.

“After the stem cell surgery, I’m able to live my life again,” the man says in a quiet, halting voice. “Thank you for giving me my life back.”

Klein turned off the video, his eyes bright.

“I wish all the voters could see this,” he said. Christopher Reeve, whom he considered a friend, “would have been absolutely ecstatic” to have seen such a video, he added.

“In 2004 we had a vision of the future and data on animals,” Klein said. “In 2020, we will have patients who were paralyzed, patients who were blind, patients with cancer who will tell their story. The public will decide.”

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