I interviewed four trailblazing researchers at the University of Minnesota Medical School for Twin Cities Business magazine. I was stunned to find out that, over the next few years, Alzheimer’s disease and type 1 diabetes may be as scarce as polio, the severe organ donor shortage may be resolved and we might be much closer to being a tobacco-free nation.
Doris Taylor’s favorite video is The Matrix, a stunning achievement which suggests the possibility of an alternate reality. No, not the film starring Keanu Reeves, but the short movie of a beating heart that was emailed to her at 3 AM by her then-colleague Harald Ott in the spring of 2005. “The sad but true fact was that it was three in the morning but I was in my office,” Taylor recalls. “Harald sent me the video and then called me. I watched the video, called him right back and said, ‘You’ve got to be kidding.’ It was a Eureka, fist-in-the-air, yes! moment.”
Why all the fuss? Because that beating rat heart may revolutionize organ transplants and save millions of lives. Through a process called whole-organ decellularization, all the cells were slowly drained from the heart, leaving only the extracellular matrix—the framework between the cells—intact. “You can think of it as a scaffold, a bare wooden frame for a house,” Taylor says.
The heart was repopulated with a mixture of progenitor cells—which, like stem cells, have the capacity to differentiate into specific types of cells—that came from neonatal or newborn rat hearts. The scaffold was then placed in a sterile lab setting and watched around the clock. Four days later, the cells began to contract; four days after that, the heart began to pump. “Take a section of this ‘new heart’ and slice it, and cells are back in there,” Taylor says. “The cells have many of the markers we associate with the heart and seem to know how to behave like heart tissue.”
If Taylor and Ott’s theory holds, a decellularized heart will become a new, healthy heart that can then be transplanted into any body that’s a good match for it. The implications are staggering. Nearly five million people live with heart failure, and about 550,000 new cases are diagnosed each year in the United States. Up to 50,000 of these patients die annually waiting for a donor heart. Since a bioartificial heart could be built in weeks, the dire shortage of donor organs could be resolved in a relative blink of an eye.
What’s more, the four-hour window from harvesting a heart to transplanting it would be a relic of the past. Most importantly, growing a person’s own stem cells and transplanting them into a heart matrix could result in a heart that matches the recipient’s body, eliminating the need for harsh anti-rejection drugs. Such drugs can damage the recipient so severely that another transplant is often required down the road.
It’s little wonder that Taylor was ecstatic when she was emailed proof that the theory she and Ott had brainstormed together had come one giant step closer to reality. Her euphoria recalls the Greek scholar Archimedes, who experienced his Eureka moment in the bathtub. “I wasn’t in a bathtub but the heart was, so there you go!” Taylor says with a laugh.
Taylor’s team may have experimented on a heart but the technology could be applied to virtually any organ. “One of our major goals is to change the lives of people who are waiting for an organ transplant and can’t get one,” Taylor says. “Along the way, we have the opportunity to do other things as well. If you think about it, building a whole organ is pretty complicated, and yet building pieces of organs may not be as complex; and because we have blood vessels in them, we can sew our pieces of organ into another organ and connect it and feed the cells. So growing a piece of heart for a kid with a congenital heart abnormality might be good enough.”
As Taylor’s team continues to advance its research, the possibilities for applications continue to grow. “We also may be able to use these organ scaffolds as potential therapies,” she says. “One of the products on the market right now is an artificial skin. If we decellularize skin, and we can, could we use that to treat burns? Could you grow your own cells back into that? Our hope is that because we can do this with any organ or any tissue that gets a blood supply, we can think about building a pancreas for kids with diabetes, we can think about building a lung for people with cystic fibrosis, we can think about building new blood vessels for bypass grafting. The potential here is huge.”
This new technology may also be a boon for the pharmaceutical industry. “We’re also looking at building tools for drug discovery,” Taylor says. “A number of drugs never make it past clinical studies because of toxicity, which is usually due to liver or heart problems. If we could take human cells and grow them on a three-dimensional scaffold and essentially make a human heart or liver or kidney in the laboratory, then we could in theory test drugs on those and eliminate the drugs that are most toxic before they ever reach a person. We’re pretty excited about that.”
Ever since Taylor and Ott’s breakthrough was made public via an online story in Nature Medicine on January 13, 2008, the medical research community has been buzzing about “the beating heart in a jar.” “There are a lot of people who are now doing similar things based on what we’ve done,” Taylor says. “I get a lot of e-mails asking me how to do it.”
Taylor has also fielded requests from a number of scientists who have asked if Taylor’s team could build scaffolds for them. “To build a new tissue or organ, you need three things,” Taylor says. “You need cells, you need a place to put those cells—a scaffold, if you will—and you need a way to feed those cells, a blood supply. With our scaffold and the fact that it’s perfusable, we’ve got two of these three. So yes, if other people have cells that they want to use to build a pancreas, we’ve got the pancreas scaffold that has a blood supply and can feed those cells.”
Taylor has also heard from people who are desperate to help their loved ones. “I get a lot of e-mails from fathers, mothers, aunts, uncles, sisters who want organs for their family member,” she says. “When you get a letter from a parent, and you’re not there yet, it’s hard. So a lot of our experiments have names on them now. I don’t mean that literally, but what I mean is we understand the people who need these and we’re working very hard to try to move forward in a smart way but as quickly as possible.”
With so many possibilities to consider, Taylor has to blend science with strategy to determine the best course of action. “It does take a lot of energy, I can tell you,” she says. “But thank goodness I don’t have to do it alone. The University of Minnesota is a great community to be in for guidance and support for figuring out what the next best step is.”
Taylor has been motivated to help people struggling with illness and disease since she was a child. Her fraternal twin brother Dan has cerebral palsy and her father died from cancer when they were only six. “I think those two things together made me want to do something that gave everyone a fair shot,” she says. “And growing up in Mississippi probably compounded that. It was a time when the world was changing and I saw a lot that made me want to make a difference. And I still do. I want to change the world.”
Watch a two-minute video of Doris Taylor explaining her work.
KAREN HSIAO ASHE
Professor of Neurology and Neuroscience ,
Director, N. Bud Grossman Center for Memory Research and Care
After studying Alzheimer’s for 16 years, Dr. Karen Hsiao Ashe wasn’t surprised when her own father began showing signs of the disease in the last year. “My father is 90 years old, so his dementia is a sad fact of statistics,” she says. “More than 50 percent of people over the age of 85 have the disease; if you live to 100, you have a 75 percent chance of getting it. Fortunately, my mother is very healthy and she’s doing a wonderful job of taking care of him at home.”
Such stark statistics underscore the importance and the urgency of Ashe’s research, which is primarily focused on preventing Alzheimer’s rather than treating the 5 million Americans already afflicted with it. “Prevention is to treatment as vaccination for polio is to the treatment of polio,” Ashe explains. “Had a vaccine not been developed for polio, hospital wards would now be filled with people needing artificial ventilators to breathe. Similarly, not only is treatment of Alzheimer’s likely to be less effective than prevention, it’s also likely to be 10 to 1000 times more expensive.”
The numbers paint a somber picture. Unless a preventive cure is found, the next 40 years will see 28 million new cases in this country and a staggering 200 million cases worldwide. People typically live 10 years with Alzheimer’s. “I chose this area of research because it’s the most important unresolved medical problem facing our country as well as of all the developing and developed nations around the world,” Ashe says.
Ashe’s research addresses the molecular basis of memory loss and cognitive dysfunction in Alzheimer’s disease. There is increasing evidence that the cognitive decline and pathological changes associated with Alzheimer’s disease develop many years before the dementia can be diagnosed, blurring the boundary between age-related memory problems and the earliest stages of Alzheimer’s disease.
There are still unanswered questions about the link between Alzheimer’s and neurodegeneration, which means loss of neurons and loss of synapses, the connections between neurons. Indeed, cognitive function often declines with age and is believed to deteriorate initially because of changes in synaptic function rather than loss of neurons. The challenge, therefore, is to distinguish the symptoms of ordinary aging from the onset of Alzheimer’s.
The maddening aspect of Alzheimer’s research is that every new discovery only makes the eventual solution that much more complex. Ashe’s team is exploring every possible configuration of known factors, but every answer they come up with only leads to more questions.
There are two main types of Alzheimer’s disease: sporadic (influenced by multiple genes), and early-onset familial (caused by mutations in single gene), the latter of which accounts for only about 2 percent of cases. “The specific genes influencing sporadic Alzheimer’s have not been identified, except for the APOE gene,” Ashe says. “There are probably a handful, maybe even a dozen or more. But although genes increase susceptibility, they do not guarantee getting the disease. And lifestyle factors may either augment or decrease your genetic risk.”
Research has long centered on the amyloid-ß (amyloid-beta) and tau proteins. To understand how these proteins impair memory and cognition, Ashe developed a mouse model back in 1996 that models the stages of Alzheimer’s preceding the onset of dementia. “We injected into mouse embryos human DNA that had been genetically engineered to simulate human DNA from Alzheimer’s patients suffering from the familial form of disease,” she explains. “We have been studying that mouse because we believe that if we can understand the stages preceding and leading up to dementia, then we might be able to prevent the disease from occurring.”
That work has shown that the aggregates of amyloid-ß and tau proteins which define Alzheimer’s disease neuropathologically do not cause cognitive deficits in mice. However, in 2006, Ashe’s team discovered a form of the amyloid-ß protein called Aß star (Aß*) that does disrupt cognitive function in mice and rats, and which revealed a potential mechanism by which interactions with a neuronal receptor may impair memory.
Pilot findings, which have not yet been confirmed in larger studies, show that Aß* is present at higher levels in brain tissue of patients with Alzheimer’s disease and MCI (mild cognitive impairment) than in individuals without cognitive impairment. Consequently, a major focus of Ashe’s lab is determining whether Aß* is a predictive marker of Alzheimer’s. “We’re now seeing a Aß* even before MCI,” Ashe notes. “Our hypothesis is that the Aß* protein initiates the disease.”
The riddle wrapped up in the enigma within the mystery is how the Aß* protein initiates Alzheimer’s. Solving that puzzle will theoretically allow doctors to prevent the damage that occurs after the Aß* protein tips over that first biological domino. “Our theory stipulates that Aß* initiates Alzheimer’s when it attaches to specialized nerve cell proteins years before symptoms appear,” Ashe explains. “We believe that the most promising area for intervention is a small molecule—a compound that you can take as a pill—that blocks the chain reaction which ultimately culminates in the development of synapse loss, neuron death and dementia.”
Further muddying the research waters is the fact that poor performance on memory tests can predict Alzheimer’s disease up to 15 years before it is diagnosed, and asymptomatic individuals at risk genetically for Alzheimer’s disease have shown evidence of brain dysfunction in functional magnetic resonance imaging.
At the heart of this brain dysfunction is the APOE gene, so far the only gene positively identified as a contributor to Alzheimer’s. There are three varieties: APOE2, APOE3 and APOE4. Every human being has two APOE genes, having inherited one from each parent.
There are six possible pairings of these APOE genes. “The more copies of APOE4 you have, the higher the risk you are for Alzheimer’s disease,” Ashe says. “However, you could have two copies of APOE4 and live to be 95 and still not get Alzheimer’s. So it’s not an all or nothing scenario, but it does definitely influence your risk.”
That “maybe it does, maybe it doesn’t” dynamic is backed up by solid evidence. “Imaging studies done by other research teams compared normally functioning people in their 50s who had APOE4 with those who didn’t have APOE4,” Ashe explains. “They were looking to see whether there were any differences in the imaging patterns that were showing up on their PET (positron emission tomography) scans or on their functional MRIs. The astonishing thing is that there were: the people who had more copies of the APOE4 gene had different patterns of brain function.”
Those imaging results prove that an individual may have brain dysfunction without exhibiting any behavioral symptoms. “That’s the scary thing, because it means that the disease may be starting long before there are symptoms,” Ashe says. “By the time you have MCI, you’ve already got symptoms by definition.”
Much work remains to be done but early results are promising. “I’m very, very excited about work that is being done not only in my laboratory but in other laboratories that will be able to block the chain reaction and prevent Alzheimer’s from developing—and in a way that is cost-effective and widely available to the world’s rich and poor,” Ashe says. “My dream is for the N. Bud Grossman Center for Memory Research and Care to take the lead in developing guidelines that ensure that Alzheimer’s prevention is a reality by the year 2020.”
Dr. Meri Firpo traces her quest to find a cure for type 1 (juvenile) diabetes all the way back to her first biology class in grade school, when she was amazed to learn that people start out as a single cell. “I wondered how the cells could divide and make more of the same cells, but then somehow start to change into different kinds of cells, like skin cells and muscle cells,” she recalls.
Now a stem-cell scientist, Firpo wants to discover how to gain control over stem cells’ division into specific cells, with the goal of improving health. It’s a formidable challenge. Stem-cell science is complex, evolving and includes several kinds of cells.
One type of stem cell, derived from embryos, was her initial focus. “Embryonic stem cells are a very special kind of cell that come from a stage of the embryo before any tissue specification has occurred,” she explains. “These cells have a unique combination of characteristics. One, they can differentiate into any cell type, which we call pluripotency. Two, they are capable of self-renewal, which is the capacity to grow and expand to many, many cells without specifying into any cell type.”
At the University of California San Francisco, Firpo directed the derivation of two embryonic stem cell lines with the intention of generating bone marrow stem cells for, among other reasons, the benefit of patients who needed transplants but had no donor. “Stem cells are very important for regenerating tissues throughout our life,” she says.” But we haven’t been very effective at getting those cells to expand outside of the body without specifying; they seem to spontaneously want to specify when we take them out of the body.”
Watching how stem cells specify in the laboratory could lead to major breakthroughs in the understanding of human development. “Being able to watch these cells in the laboratory specify into different tissues gives us essentially a model of human development,” Firpos says. “We could then manipulate the cells genetically or manipulate the environment to help us understand where those processes go wrong and lead to disease. If we can culture these cells indefinitely so that they remain embryonic stem cells with the capacity to make any cell type in the body, we could then make enough tissues from them to transplant into patients whose cells had been damaged.”
Diabetes research was a natural extension of Firpo’s work. “I hadn’t really thought about diabetes as a next goal,” she says. “I was focusing on research into bone marrow and the blood. But I was asked by my colleagues in the diabetes research community to apply our successful techniques from bone marrow transplant to try to generate a stem cell transplantation therapy for type 1 diabetes.”
At the heart of that therapy are pancreatic islet cells. The pancreas produces enzymes that squirt into the small intestine through a duct system to aid digestion. Within the pancreatic tissue that performs this digestive function are small clumps of cells that are unconnected to the duct system.
These cells, called the Islets of Langerhans, number about one million in a healthy adult human and make up less than 2 percent of the pancreas’ mass. There are a handful of different cell types within the islets, which secrete various hormones directly into the blood; these hormones regulate each other as well as the level of glucose in the blood.
One of the cell types, the beta cell, secretes insulin, the hormone that’s released after a person eats to signal to their cells to take up glucose to use for energy or to store as fat. In type 1 diabetes, the immune system attacks the beta cells—and only the beta cells—so that the body cannot produce insulin, causing the glucose to stay in the blood and become toxic.
Essentially, the Islets of Langerhans behave like a mini organ within the pancreas. “Replacing the islets is one way of treating diabetes,” Firpo says. “That therapy is actually available already; you can receive an islet transplant from a human cadaver, and the immunosuppression that’s required to keep your body from rejecting that transplant also prevents the auto-immune attack of the diabetes.”
Intrigued, Firpo began working with diabetes researchers to gain a better understanding of the disease and of human pancreatic development in order to generate an islet transplantation therapy. Her work led her to accept a position at the University of Minnesota in 2005. “It was a good fit,” she says. “The U of M’s transplant program for islets, run by Dr. Bernhard Hering, is the best. And Catherine Verfaillie, who at the time was the director of the Stem Cell Institute at the University of Minnesota, which was the first of its kind in the world, had asked me to come here and work with her in parallel.”
The major hurdle in islet transplantation is that the number of type 1 diabetics far outstrips the supply of human cadaver donors. “By potentially generating large numbers of stem cells for diseases like diabetes, these cells could be transplanted and potentially cure diseases that, in many cases, have limited donors,” Firpo says. “So these cells are incredibly useful scientifically but also potentially therapeutically.”
Firpo’s work received a huge boost in December when Best Buy founder Richard Schulze donated $40 million to the University of Minnesota to investigate possible cures for type 1 diabetes. Two of the three projects on that grant are being directed by Hering, who is studying the effectiveness of transplanting specially nurtured pig islets into humans.
The third project, directed by Firpo, will attempt to generate islets from various stem cell sources, and particularly lab-induced pluripotent cells, that could ultimately be transplanted. “The work in this project is with a different type of pluripotent stem cell,” Firpo notes. “One of the limitations of working with embryonic stem cells is that you can only identify a disease model embryo if you can do the genetic test on the individual embryo. Diabetes has no genetic test, so we are going to use a different approach to create pluripotent stem cell lines by reprogramming adult cells back to a state similar to an embryonic stem cell.”
That methodology will enable Firpo to make a disease-model pluripotent line from people who already have diabetes, which eliminates the need for a genetic test. It will also allow her to investigate whether it’s possible to generate pluripotent stem cells from a patient’s own tissues, which theoretically could cure the patient’s diabetes with their own cells.
Pre-clinical testing with mice and non-human primates is already under way. “We have encouraging results that we would like to apply to this new stem cell technology,” Firpo says. “But it’s very challenging and we have a lot of work to do.”
Dorothy Hatsukami is a big-picture thinker, which is why she dedicated her career to combating tobacco addiction. “I’m in the business of preventing disease,” she says. “I thought I could make the biggest health impact by helping people who want to quit smoking.”
The numbers back her up. More than 400,000 deaths per year in this country are associated with tobacco use, as is 20 percent of chronic heart disease, 80 percent of pulmonary disease and 30 percent of all cancers, including more than 80 percent of lung cancers. “If we can prevent tobacco addiction, we can really reduce the disease burden in this country and even worldwide,” Hatsukami says.
She has her work cut out for her—there are roughly 1.2 billion smokers in the world. If nothing is done to control the spread of the tobacco epidemic, there will be a projected 10 million tobacco-related deaths per year by 2025. “That’s why I’m so passionate about dealing with tobacco addiction,” Hatsukami says. “We can also make an impact economically by reducing health care costs and loss of job productivity.”
It’s hard to believe that when Hatsukami started researching nicotine addiction more than 25 years ago, there was little information available about the addictive nature of nicotine. Though it would seem obvious, there was not a unanimous consensus that nicotine was addictive, primarily because of the absence of some of the symptoms typically associated with addiction. “People who are addicted to nicotine don’t have the kind of social or job consequences you might see among those who have other types of addictions,” Hatsukami notes. “On top of that, you don’t see the intoxication as the result of drug use.”
Hatsukami’s team was one of the first to scientifically characterize the withdrawal symptoms experienced by smokers when quitting smoking, proving that smokers develop a physical dependence on nicotine. This finding led her to study medications that may reduce this physical dependence. More than a quarter century later, one of Hatsukami’s priorities is focusing on how to reduce tobacco toxin exposure in nonsmokers.
Her team’s research made headlines in March 2008 by releasing a study showing that hospitality workers had significantly fewer tobacco-specific cancer-causing chemicals in their system after the Freedom to Breathe Act, which prohibited smoking in virtually all public places in Minnesota, went into effect on October 1, 2007. The study included nonsmoking employees of bars, restaurants and bowling alleys throughout the state.
Urine samples taken before and after the smoking ban went into effect showed that participants experienced an 83 percent decrease in cotinine (a measure of nicotine exposure) and an 85 percent decrease in NNAL, a byproduct of a potent lung cancer-causing toxin. “That shows that the Minnesota comprehensive smoking ban does make a significant difference in protecting our workers from harm,” Hatsukami says. “I’m really proud of the fact that our state was able to pass that ban.”
Hatsukami was also part of a research team led by Dr. Stephen Hecht that proved that infants inhale the cancer-causing chemicals found in secondhand smoke. The team examined urine samples from 144 infants, all less than one year old. They found significant levels of NNAL in the urine of 47 percent of the infants who were exposed to cigarette smoking at home. Some of the infants had levels similar to those found in adult smokers.
Thanks to a Robert Wood Johnson Foundation grant specifically devoted to the dissemination of study results from an NIH grant focused on tobacco toxicity, Hatsukami’s team tirelessly works to impact policies and programs at every level. “Dissemination is vitally important,” Hatsukami says. “For example, we would like to have information about the infant study conveyed to parents who smoke to let them know that they may be doing harm to their children.”
As part of the NIH grant, researchers at the Masonic Cancer Center are also working on a number of other promising initiatives, including exploring whether the toxicity in tobacco products can be reduced for those users who are unable or unwilling to quit. “We are asking what we can do to help those individuals,” Hatsukami says. “Of course, our message is that quitting smoking is the best way, and the only known way, to reduce the mortality and morbidity associated with tobacco use.”
Hatsukami is appalled that tobacco companies can do what they please with their products. “It’s outrageous that there aren’t any performance standards,” she says. “There’s no regulation of tobacco products. The tobacco companies are able to put as many toxins in their products as they want. And there’s no regulation that requires tobacco companies to inform consumers about what’s in the products and the extent of toxicants in the products. It’s just amazing that that’s allowed.”
Those freewheeling days may soon be over. “We are trying to provide the science to push for tobacco product regulation,” Hatsukami says. “That may be just around the corner because there is a bill in front of the U.S. Congress that would give jurisdiction to the FDA to regulate tobacco products.”
Perhaps Hatsukami’s most exciting project is the development of a nicotine vaccine. Dr. Paul Pentel, one of Hatsukami’s colleagues, came up with the idea more than a decade ago. “The vaccine is basically a nicotine molecule that’s attached to a foreign carrier protein,” Hatsukami says. “The vaccine stimulates the immune system to create antibodies so that when an individual smokes, the antibodies capture the nicotine molecule. That molecular complex is so big that it can’t penetrate through the blood-brain barrier, which prevents it from getting into the brain. And if you don’t get nicotine into the brain, people won’t get the pleasure from smoking.”
Hatsukami led a study that showed that the vaccine produced anti-nicotine antibodies, was well tolerated and caused few side effects in humans. What’s more, the vaccine did not seem to cause cigarette withdrawal symptoms, and participants receiving the vaccine did not puff harder or smoke additional cigarettes to compensate for the lower levels of nicotine being delivered to the brain.
In a recent NIH-funded clinical trial of the vaccine with a biopharmaceutical company, the participants who developed high levels of antibodies after being injected with the vaccine had greater rates of cessation than those people who were given a placebo—roughly 25 percent to 12 percent. “The real scientific challenge now is to try to produce high antibodies in the majority of people who are injected with the vaccine,” Hatsukami says.
Hatsukami enjoys not only her work, but the opportunity to work alongside so many other passionate people. “The most rewarding part of my research career is having such terrific collaborators,” she says. “It’s exciting to sit down and come up with research projects that help us better understand nicotine addiction and its consequences and that potentially have an impact on public health.”
ABOUT PHIL BOLSTA
Phil is the author of Through God’s Eyes: Finding Peace and Purpose in a Troubled World, a comprehensive guide to living a spiritual life. Who will benefit from reading it?
Anyone who is on a spiritual path, or wants to start one
Anyone who loves life, or wants to learn how to
Anyone who is happy, or wants to be happier
Here is a two-minute video introduction to Through God’s Eyes.
• an overview of the book
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• the Foreword by Caroline Myss
• my Introduction
• chapter excerpts
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Phil is also the author of Sixty Seconds: One Moment Changes Everything, a collection of 45 inspiring, life-changing stories from prominent people he interviewed, including Joan Borysenko, Deepak Chopra, geneticist Dr. Francis Collins, acclaimed sportswriter Frank Deford, Dr. Larry Dossey, Wayne Dyer, Dan Millman, Caroline Myss, Dr. Christiane Northrup, Dr. Dean Ornish, Dr. Rachel Naomi Remen, Dr. Bernie Siegel, James Van Praagh, singer Billy Vera, Doreen Virtue, Neale Donald Walsch, and bassist Victor Wooten.
Reading this book is like spending a few minutes face to face with each of the contributors and listening to their personal stories. Click here to read unsolicited testimonials from readers. Learn more by visiting the official Sixty Seconds website.
Sixty Seconds was one of three finalists in the General Interest/How-To category at the 12th annual Visionary Awards presented by COVR (Coalition of Visionary Resources) in Denver on June 27, 2009.