In 1999, Konrad Hochedlinger squeezed into a packed lecture at the Institute of Molecular Pathology in Vienna to hear stem cell researcher Rudolf Jaenisch talk about nuclear transfer cloning techniques. Hochedlinger, a biology masters student, knew little about cloning, but he’d been intrigued by the technique ever since scientists cloned Dolly the sheep in 1996. “I was too shy” to talk to Jaenisch then, he says. But months later Hochedlinger stopped by Jaenisch’s office at the Massachusetts Institute of Technology’s Whitehead Institute for a chat. He ended up sticking with Jaenisch for six years.

Hochedlinger joined Jaenisch’s lab at “a very fruitful and productive time,” he says. He worked closely with fellow graduate student Kevin Eggan and postdoc William Rideout. The three published a slew of papers demonstrating how nuclear transfer triggers epigenetic reprogramming. “Konrad was pretty amazing in his diligence,” says Rideout, now at AVEO Pharmaceuticals. “He was an eager learner and very enthusiastic about the work we were doing.”

Hochedlinger’s PhD project tested whether fully differentiated cells or just adult stem cells could give rise to cloned animals. “It was a very risky project because it was totally unclear whether it would work or not,” Hochedlinger says. It failed for over a year, but eventually he managed to clone mice from the nuclei of B and T cells, proving that terminally differentiated cells can be reprogrammed.1

“I thought it wouldn’t work,” Jaenisch says. “But it’s typical for [Hochedlinger] to pull through with complex experiments.”

After graduating, Hochedlinger stayed on for a postdoc with Jaenisch. In 2004, he transformed melanoma cancer cells into normal embryonic stem cells using nuclear transfer. And in 2005, he activated the Oct4 gene in adult mouse cells, showing that this transcription factor prevented adult stem cells from differentiating.2

In 2006, Hochedlinger started his Harvard Medical School lab. Around the same time, Kyoto University’s Shinya Yamanaka reported that mouse skin cells could be reset to behave like embryonic stem cells by adding just four transcription factors, including Oct4. Many researchers were skeptical, but “I knew right away that it was important,” says Hochedlinger. “I had all the expertise and tools from my previous work” to create these induced pluripotent stem (iPS) cells. “Within a few months, we were not only able to reproduce the results but to improve the technology,” he says.

The efficiency of the reprogramming was frustratingly low, Hochedlinger recalls. He tried to address this by switching the delivery vehicle from retroviruses, which integrate into the genome, to adenoviruses, which do not. The efficiency was still “dismal,” Hochedlinger says, but he had successfully devised the first-ever protocol to generate iPS cells without viral integration, thereby bringing iPS cells one step closer to the clinic.3

Hochedlinger now finds himself working in one of the hottest fields in biology. “It’s exciting on the one hand to be a part of it and to be a player, but it’s also quite competitive,” he says. Even so, “the fun outweighs the competitive aspect.”

Title: Assistant Professor, Department of Stem Cell and Regenerative Biology, Massachusetts General Hospital and Harvard Medical School

Age: 33

Representative publications:

1. K. Hochedlinger and R. Jaenisch, “Monoclonal mice generated by nuclear transfer from mature B and T donor cells,” Nature, 415:1035–38, 2002. (Cited in 206 papers)

2. K. Hochedlinger et al., “Ectopic expression of Oct-4 blocks progenitor-cell differentiation and causes dysplasia in epithelial tissues,” Cell, 121:465-77, 2005. (Cited in 111 papers)

3. M. Stadtfeld et al., “Induced pluripotent stem cells generated without viral integration,” Science, 322:945-49, 2008. (Cited in 34 papers)

Robert Lanza, M. D. is considered one of the leading scientists in the world. He is currently Chief Scientific Officer at Advanced Cell Technology, and Adjunct Professor at Wake Forest University School of Medicine. He has hundreds of publications and inventions, and over 20 scientific books: among them, “Principles of Tissue Engineering,” which is recognized as the definitive reference in the field. Others include One World: The Health & Survival of the Human Species in the 21st Century (Foreword by former President and Nobel laureate Jimmy Carter), and the “Handbook of Stem Cells” and “Essentials of Stem Cell Biology,” which are considered the definitive references in stem cell research.

Dr. Lanza received his BA and MD degrees from the University of Pennsylvania, where he was both a University Scholar and Benjamin Franklin Scholar. He was also a Fulbright Scholar, and was part of the team that cloned the world’s first human embryo for the purpose of generating embryonic stem cells. In 2001 he was also the first to clone an endangered species (a Gaur), and in 2003, he cloned an endangered wild ox (a Banteng) from the frozen skin cells of an animal that had died at the San Diego Zoo nearly a quarter-of-a-century earlier. Lanza and his colleagues were also the first to demonstrate that nuclear transplantation could be used to reverse the aging process and to generate immune-compatible tissues, including the first organ tissue-engineered from cloned cells.

One of his most recent successes was showing that it is feasible to generate functional oxygen-carrying red blood cells from human embryonic stem (hES) cells. The blood cells were comparable to normal transfusable blood and could serve as a potentially inexhaustible source of “universal” blood. Dr. Lanza has also succeeded in getting stem cells to grow into retinal cells. Using this technology some forms of blindness may be curable. His team also discovered how to generate functional hemangioblasts – a population of “ambulance” cells- from hES cells. In animals, these cells quickly repaired vascular damage, cutting the death rate after a heart attack in half and restoring the blood flow to ischemic limbs that might otherwise have to be amputated. Recently, Lanza and a team lead by Kwang-Soo Kim at Harvard University reported a safe method for generating induced pluripotent stem (iPS) cells. Human iPS cells were created from skin cells by direct delivery of proteins, thus eliminating the harmful risks associated with genetic manipulation. This new method provides a potentially safe source of patient-specific stem cells for translation into the clinic. However, one of his greatest early achievements came from his demonstration that techniques used in preimplantation genetic diagnosis could be used to generate hES cells without embryonic destruction.

Dr. Lanza has received numerous awards, including a Rave Award for medicine, and an “All Star” award for biotechnology. Lanza has been called the “Bill Gates of Science. He believes that stem cell technology will have a substantial importance in the future of medicine. According to Discover magazine, “Lanza’s single-minded quest to usher in this new age has paid dividends in scientific insights and groundbreaking discoveries.” Dr. Lanza and his research have been featured in almost every media outlet in the world, including CNN, TIME, Newsweek, People, as well as the front pages of the New York Times, Wall Street Journal, Washington Post, among others. Lanza has worked with some of the greatest thinkers of our time, including Nobel laureates Gerald Edelman and Rodney Porter, renowned Harvard psychologist B.F. Skinner (the “Father of modern behaviorism”), Jonas Salk (discoverer of the Polio vaccine), and heart transplant pioneer Christiaan Barnard. His current research and work at Advanced Cell Technology focuses on stem cells and regenerative medicine and their potential to provide therapies for some of the world’s most deadly and debilitating conditions.

In 2007, Lanza published a feature article, “A New Theory of the Universe” in The American Scholar, a leading intellectual journal which has previously published works by Albert Einstein, Margaret Mead, and Carl Sagan, among others. His theory places biology above the other sciences in an attempt to solve one of nature’s biggest puzzles, the theory of everything that other disciplines have been pursuing for the last century. Nobel laureate E. Donnall Thomas stated “Any short statement does not do justice to such a scholarly work. The work is a scholarly consideration of science and philosophy that brings biology into the central role in unifying the whole.” This new view has become known as Biocentrism. In biocentrism, space and time are forms of animal sense perception, rather than external physical objects. Understanding this more fully yields answers to several major puzzles of mainstream science, and offers a new way of understanding everything from the microworld (for instance, the reason for Heisenberg’s uncertainty principle and the double-slit experiment) to the forces, constants, and laws that shape the universe.

“Robert Lanza is the living embodiment of the character played by Matt Damon in the movie “Good Will Hunting.” Growing up underprivileged in Stoughton, Mass., south of Boston, the young preteen caught the attention of Harvard Medical School researchers when he showed up on the university steps having successfully altered the genetics of chickens in his basement. Over the next decade, he was “discovered’ and taken under the wing of scientific giants such as psychologist B.F. Skinner, immunologist Jonas Salk, and heart transplant pioneer Christiaan Barnard. His mentors described him as a “genius,” a “renegade thinker,” even likening him to Einstein.” – U.S.News & World Report, cover story.

Dr. West is the Chief Executive Officer of BioTime, Inc. (OTCBB: BTIM) and Embryome Sciences, Inc. of Alameda, California. The Companies are focused on developing an array of research and therapeutic products using human embryonic stem cell technology.

He received his Ph.D. from Baylor College of Medicine in 1989 concentrating on the biology of cellular aging. He has focused his academic and business career on the application of developmental biology to the age-related degenerative disease. He was the Founder of Geron Corporation of Menlo Park, California (Nasdaq: GERN) and from 1990 to 1998 he was a Director, and Vice President, where he initiated and managed programs in telomerase diagnostics, oligonucleotide-based telomerase inhibition as anti-tumor therapy, and the cloning and use of telomerase in telomerase-mediated therapy wherein telomerase is utilized to immortalize human cells.

From 1998 to 2007 he was President and Chief Scientific Officer at Advanced Cell Technology, Inc. (OTCBB: ACTC) where he managed programs in animal cloning, human somatic cell nuclear transfer, cell differentiation, and ACTCellerate, a technology for the multiplex derivation and characterization of clonal human embryonic progenitor cell lines.

I want to know where blood comes from. Biologically, the blood (hematopoietic) system is fantastically intricate. The complexity of how it’s regulated and responds to environmental stresses is on par with any other tissue or organ. All the parts of the body work together in a delicately balanced system of life. However, blood is among a select few parts of the body with additional, symbolic meaning. It is blood that is seen to carry our passions. It is blood that is used to identify our descendants (eg. our bloodline). It is blood that marks those among us with whom we enter into sacred kinships (eg. blood brothers). Literature contains abundant references to blood as a vehicle for understanding deeper human significance. As Sitwell said, “Blood is that fragile scarlet tree we carry with us.” Works like Macbeth, The Blank Page (Karen von Blixen), and of course Dracula are just a few examples of how human kind sees blood as something more than cells and plasma pulsing through our vessels. Blood’s metaphorical nature alone is worthy of study.

That said, blood is clearly more than poetically significant. People have studied the blood, both healthy and otherwise, for centuries. From Paracelsus’ comments on splenomegally in the 1500′s to the famous clotting disease of the Romanovs in Russia (and other royal households), what blood does, and how it does it, is of great scientific and medical interest. My background is in genetics and my particular research tries to understand what genes are involved in blood cell production, how that happens at the earliest stages when the first blood cell is made from its non-blood precursor, and how the entire process goes astray in disease. I do this work using human pluripotent stem cells of many types.

The specific use of pluripotent stem cells is key to my work for at least two reasons: (1) I am interested in understanding the pathophysiology of human genetic diseases of the blood and (2) pluripotent stem cells are capable of making any type of cell in our bodies, but have yet to do it; they are a blank slate. Adult blood stem cells are eventually made in nature from a cell like a pluripotent stem cell and I want to understand how that works. The incredible developmental plasticity of pluripotent stem cells makes them perfect platforms for studying how one cell (the fertilized egg) is able to divide and make all of the hundreds of different types of cells in our bodies. This is the central question of developmental biology.

However, the use of human pluripotent stem cells for research has renewed a centuries old debate into what it means to be human and also how far science should be allowed to go in order to combat human frailty. As such, the consideration of areas beyond, yet impacting science is of keen interest to me. Ethics, philosophy, scientific conduct, public policy, history, and education are important things that I also do my best to study and be engaged with as part of my research.

Finally, I have a growing interest in germ cell-related tumors including teratomas, teratocarcinomas, and similar masses as these naturally-occuring entities originate from pluripotent cells.

Like a movie with multiple plots spiraling around an intriguing lead character, George Daley’s scientific career centers on a major player in human biology—the cell that creates the entire array of blood cells.

The hematopoietic stem cell (HSC), which gives rise to the progenitors of all the differentiated, specialized blood cells, is at center stage in Daley’s laboratory. Research in his lab and others has shown that the HSCs can have both positive and negative influences on the course of some diseases.

In some of his earliest research, Daley showed that an oncogene known as Bcr-Abl, which spurs malignant growth of HSCs and overproliferation of white blood cells, is responsible for chronic myelogenous leukemia (CML). Bcr-Abl is created when two normal chromosomes inappropriately swap genetic material. The highly successful drug Gleevec (imatinib) can restore the normal ratios of blood cells by blocking Bcr-Abl’s errant growth signals, but many patients become resistant to the drug when new mutations arise.

In more recent studies, Daley and his colleagues identified many of the changes that confer resistance to Gleevec. Now, his research group is devising methods to detect these mutations and is evaluating drugs that target them. Of special interest, Daley says, is a “mutation from hell” that makes relapses in CML patients very difficult to treat.

Although the master blood stem cell is at the heart of CML, the regenerative power of even more versatile stem cells underlies some of the most exciting prospects in biomedicine—correction of genetic disease and the potential to regenerate healthy tissue to repair damage in the brain, heart, pancreas, and other organs.

What Daley has learned about how Bcr-Abl sends blood stem cells down a cancerous path was crucial to understanding how normal HSCs are generated from the true master cells of the body—embryonic stem cells. “Back in 1990, when I was in David Baltimore’s laboratory at the Whitehead Institute, I began treating mouse embryonic stem cells with different kinds of serum and getting them to become blood cells in a Petri dish,” Daley recounts. “Even then I was thinking that if you could make the complete hematopoietic lineage, you would have a universal donor cell for bone marrow transplantation.”

Thus far, Daley and his colleagues have been able to make blood stem cells that will regenerate a new blood-forming system in mice—a step toward a universal marrow transplant source—but not without certain genetic manipulations. “We’re still missing some of the key elements of the differentiation program that would allow us to understand how embryonic stem cells produce HSCs,” he says.

While continuing to study these questions, Daley has always kept his eyes on the bigger goal of reprogramming adult tissue cells from an individual patient so they revert to an embryonic state. Once in this more primitive state, the adult cells can theoretically be coaxed into developing as healthy replacement tissues.

Daley and others are refining and testing several approaches to make reprogramming more efficient. One approach relies on a technique called nuclear transfer, in which the nucleus of an adult cell from a mouse with a genetic blood disease is placed into a hollowed-out human egg cell containing natural factors that reprogram the nucleus, creating a new embryo. Embryonic stem cells removed from the embryo are then grown in culture, where the genetic flaw is repaired. Researchers can then direct the cultured stem cells, by chemical and other means, to produce HSCs that can regenerate a healthy blood system in the mouse, curing the disorder. The Daley group has accomplished this with a genetic immune disease in mice, but so far the process is extremely inefficient.

Another powerful technique, parthenogenesis, does not require a donor nucleus. Eggs, or oocytes, are artificially stimulated to duplicate their chromosomes, resulting in an embryo for cell regeneration therapy that can be tailored to be immunologically compatible with any recipient. Daley ultimately envisions “banks” of master cells and tissues for matching to specific patients, but the transplantation work is currently in a basic modeling stage in animals, he says.

A third strategy under investigation in Daley’s lab involves nuclear transfer using animal instead of human oocytes to get around the shortage of human eggs.

In parallel with his research, Daley has been an articulate and authoritative voice in the public discussion of stem cell research and its future prospects. He is often invited to speak at public forums and has testified before Congress in support of fewer governmental restrictions on research with human embryonic stem cells. He was elected president of the International Society for Stem Cell Research (ISSCR) for 2007–2008 and headed the ISSCR committee that published international guidelines for the ethical and responsible conduct of research with stem cells.

Because of restrictions on federal funding of research on embryonic stem cells derived from cell lines not approved by the Bush administration, “we remain excessively constrained in the United States in the kinds of questions we can ask,” says Daley, who receives some private research support from the Harvard Stem Cell Institute and Children’s Hospital. “It is tremendously exciting that the HHMI funding will give me greater flexibility to do research on `nonpresidential’ cell lines and take it in a direction that won’t be as limited.”

George Daley is Associate Professor of Biological Chemistry at Harvard Medical School and Associate Professor of Pediatrics at Children’s Hospital Boston. He received his A.B. in biology from Harvard University, his Ph.D. in biology from Massachusetts Institute of Technology, and his M.D. from Harvard Medical School. He is the recipient of a Burroughs Wellcome Fund Clinical Scientist Award in Translational Research, the Judson Daland Prize of the American Philosophical Society for achievement in patient-oriented clinical research, and an NIH Director’s Pioneer Award.

Original Article