Developed by the Federation of American Societies for Experimental Biology (FASEB) to educate the general public about the benefits of fundamental biomedical research. INSIDEthis issue Life’s Blood: in Health and Disease Pumps and Pipes, Frogs and Fish 2 Watching Through Windows 4 Dynamic Plumbing: Angiogenesis and Adaptation 5 Blood and Tumors 6 The Search for Factors: Alphabet Soup 9 Switch Off, Switch On 11 From Finding Factors to Drug Development 12 Into the Clinic and the Headlines 13 Beyond 15 Promoting Angiogenesis to Save Legs and Lives 15 More to Be Done 17 Acknowledgments Life’s Blood: Angiogenesis in Health and Disease

Author, Jacqueline Jaegar Houtman, Ph.D.

Scientific Advisors, Robert J. Tomanek, Ph.D., University of Iowa, Carver College of

Joseph C. LaManna, Ph.D., Case Western Reserve University, School of Medicine

Scientific Reviewer, Paula Dore-Duffy, Ph.D., Wayne State University, School of Medicine

BREAKTHROUGHS IN BIOSCIENCE COMMITTEE

James E. Barrett, Ph.D., Chair, Drexel University College of Medicine

David Brautigan, Ph.D., University of Virginia, School of Medicine

Rao L. Divi, Ph.D., National Cancer Institute, National Institutes of Health

Marnie Halpern, Ph.D., Carnegie Institution of Washington

Tony T. Hugli, Ph.D., Torrey Pines Institute for Molecular Studies COVER: Angiogenesis, or the formation of new blood ves- sels, plays a critical role in a number of diseases and condi- Mary Lou King, Ph.D., University of Miami School of tions, including cancer, diabetic , and wound Medicine healing. Decades of basic research discovery, from studying Fred R. Naider, Ph.D., College of Staten Island, CUNY blood vessels through the thin membrane of a rabbit’s ear Loraine Oman-Ganes, M.D., FRCP(C), CCMG, FACMG, to detailing the mechanism of how human blood vessels are RBC Insurance, Toronto, Canada formed, have contributed to a wide range of modern day therapies, based on increasing or decreasing angiogenesis. Robert N. Taylor, M.D., Emory University School of Images from iStock Photo. Medicine

BREAKTHROUGHS IN BIOSCIENCE PRODUCTION STAFF

Science Policy Committee Chair: Joseph LaManna, Ph.D.,

Managing Editor: Carrie D. Wolinetz, Ph.D., Director of Scientific Affairs and Public Relations,, FASEB Office of Public Affairs

Production Staff: Lawrence Green, Communications Specialist, FASEB Office of Public Affairs ALife’sn Blood:gio Angiogenesisgenesis in Health and Disease

Discovery consists of seeing what everybody has seen, and thinking what nobody has thought. Albert Szent-Gyorgi, 1937 recipient of the Nobel Prize in Physiology or Medicine

Our cells need and tissues or, conversely, if blood essary oxygen and nutrients to nutrients to survive. The cells of vessels grow too exuberantly the cells? Decreased blood flow very small organisms can obtain (Table 1). to the legs and feet is a symptom what they need from the envi- What happens when circulation of diabetes or the buildup of ath- ronment by simple diffusion, in is insufficient to provide the nec- erosclerotic plaques in the arter- which nutrients and gases pass from areas of high concentration Diseases related to Diseases related to to low concentration through cell membranes. But diffusion isn’t insufficient angiogenesis excessive angiogenesis very useful over distances greater • Alzheimer’s disease • Cancer than a millimeter or so. Larger • Amyotrophic lateral • Multiple sclerosis animals, including humans, need sclerosis (ALS or Lou • Vascular malformations a vascular system, a way for the Gehrig’s disease) • Obesity • Diabetes • Psoriasis oxygen and nutrients to get from • Atherosclerosis • Warts the outside environment to every • Hypertension • Allergic dermatitis cell in the body (and for carbon • Crohn’s disease • Kaposi’s sarcoma in AIDS dioxide and waste products to get • Lupus • Diabetic retinopathy back out to the environment). • Preeclampsia • Primary pulmonary • Nephropathy hypertension Cells grow and multiply, and • Chronic wounds • Asthma they die. Their metabolic rates • • Cystic can change, which changes their • Diabetic ulcers • Inflammatory bowel disease requirements for oxygen and • Periodontal disease nutrients. The vascular system • Liver cirrhosis • can adapt to the body’s changing • Ovarian cysts needs by changing the amount of • Uterine bleeding blood it delivers to the tissues. • Arthritis The formation of new blood ves- • Osteomyelitis sels, a process called angiogen- • Diabetic nephropathy esis, needs to be highly regulated, Table 1 – Examples of diseases related to problems with angiogenesis: The loss of con- and poorly regulated angiogen- trol over angiogenesis (the formation of new blood vessels) can lead to a large number esis can have detrimental effects. of disease states. This is true both when insufficient angiogenesis occurs or when blood vessels grow excessively. Many scientists and physicians believe that understanding and Disease can occur if there are not controlling angiogenesis is a unifying approach to treating a wide variety of diseases. enough blood vessels to feed the Adapted from Carmeliet, P. 2005. Nature 438, 932-936.

Breakthroughs in Bioscience 1 ies of the legs. Insufficient blood are leading to new strategies for pump, propelling blood to the supply can result in delayed heal- treating these diseases. But these tissues via the arteries and back ing of wounds as well as pain, breakthroughs have been built on to the via the veins, much numbness, or leg weakness, and nearly four centuries of funda- as water is transported through the affected limb may ultimately mental research on angiogenesis, pipes. How the outgoing pipes have to be amputated. as generations of scientists have were connected to the incoming asked the question: how do blood pipes remained a mystery until Decreased blood flow to the vessels grow? 1661, when Marcello Malpighi heart due to atherosclerosis or used the newly invented micro- a clot can damage or kill heart scope to observe tiny muscle, resulting in symptoms Pumps and Pipes, Frogs connecting the smallest arteries such as angina (chest pain) and and Fish and veins. At around the same shortness of breath. In its most In 1628, William Harvey pro- time, Antony van Leeuwenhoek dire consequence, cellular dam- posed the idea that blood circu- examined the circulatory systems age due to insufficient oxygen lated, with the heart acting as a of tadpoles, fish, rooster combs, may lead to a myocardial infarc- rabbit ears, and bat wings. In a tion, otherwise known as a heart letter, he noted that “the passage attack. Decreased blood flow to A of the blood from the arteries the brain may have similarly dire into the veins of the tadpole, is consequences, including stroke. not performed in any other than On the other hand, what hap- those vessels, which are so min- pens if the formation of blood ute as only to admit the passage vessels is too exuberant? One of a single globule at a time, we consequence is blindness. In the may conclude that the same is U.S., diabetic retinopathy is the B performed in like manner in our leading cause of blindness in own bodies, and in those of other adults of working age, and age- animals.” related is As the quality and power of the leading cause of blindness microscopes increased, blood in elderly adults. Both are the vessels could be observed in result of abnormal growth of greater detail. It wasn’t until late new blood vessels in the eye. C in the 19th century that it was In these neovascular diseases, confirmed that capillaries had the new blood vessels that form walls consisting of a single layer beneath the (the back of of cells and a basement mem- the eye, where light is converted, brane (Figure 2). It is through the via electrical/chemical signals, thin walls of the capillaries that to nerve impulses that then go to the exchange of material between the brain) are fragile and often the blood and the tissues occurs. leak, disrupting and damaging Figure 1 – Diabetic retinopathy: Ophthalmoscope views of a normal The vascular endothelial cells the eye tissue, resulting in vision retina (A) and those from patients suf- that make up the walls of the loss (Figure 1). We also now fering from diabetic retinopathy (B, C). capillaries also line the insides of Retinopathy, or abnormal angiogenesis know that cancerous tumors are larger vessels and the inner sur- dependent upon angiogenesis for ( growth) in the retina, is a symptom of diabetes. The retina face of the heart. growth and (spread- develops an excess of blood vessels (B), ing). which are fragile and leak, causing hem- Techniques for visualizing orrhages (red spots seen in C) that can tissues under the microscope Recent breakthroughs in our lead to blindness. Photo credit: Science continued to advance. By inject- understanding of angiogenesis Photo Library.

Breakthroughs in Bioscience 2 Blood Vessel Structure ing dyes or other chemicals into an animal’s ,

Fibrous researchers could trace the circu- outer layer itous routes taken by the smaller blood vessels under the micro- Fibrous outer layer with scope. Eventually, the electron Smooth muscle elastic fibres with elastic fibres microscope provided even more

Lumen Single layer detail. However, even the most of Lumen sophisticated of these techniques Endothelium Endothelium required tissue to be removed ARTERIES CAPILLARIES VEINS from the animal after death.

Figure 2 – Structure of a blood vessel: Arteries, which carry blood away from the heart, By choosing relatively trans- and veins, which return blood to the heart, are connected to each other and other tis- parent tissues as a sort of living sues by very small blood vessels called capillaries. Capillaries are made of single layer of microscope slide, investigators cells, called endothelium (singular = endothelial), and a . Figure were able to observe blood cells design by Corporate Press. tumbling in single file through Figure 3 – Single blood cell the capillaries (Figure 3). In the moving through a : middle of the 19th century, sci- This electron micrograph entists like Marshall Hall and shows a cross section of a capillary that is just wide Augustus Waller watched capil- enough to let the red blood laries in action in frogs’ feet and cell shown to pass through. tongues (Figure 4). An advantage The green, single layer of to studying the living animal is epithelial cells make up the capillary wall. Photo credit: that you can observe changes in Dennis Kunkel Microscopy, the same animal over time. A Inc. microscope slide is just a snap- shot of what we now know is a highly dynamic process. Not only did scientists see blood cells move through the capillaries, but they found that capillaries them- selves can change over time. As early as 1844, Platner observed capillaries in the tails of tadpoles and newts sprouting from exist- ing blood vessels and joining with other capillaries. In 1918, Eliot Clark published a detailed study of the capillaries in the tails of individual tadpoles over the course of several weeks. Figure 4 – Early studies of blood vessel development in frogs: In the 1830s and 40s, As Clark observed his tadpoles, scientists Marshall Hall and Augustus Waller observed and recorded capillary struc- he made careful drawings of ture and function in the transparent tissue found in the feet and tongues of frogs. By observing these tiny vessels in living animals, researchers were able to see blood cells the changes he saw. Vessels moving through the capillaries and the formation of new vessels over time. Source: sprouted, grew, and atrophied Hwa, C. and Aird, W.C., 2007, Am J Physiology Heart Circ Physiol, 293. Used with per- and Clark concluded that “devel- mission.

Breakthroughs in Bioscience 3 opment into the complicated and inserted genes into nicely balanced system of the that cause the blood vessels to New blood vessels can be formed under many adult animal comes to be depen- fluoresce. These fish are used different circumstances— dent upon the mechanical factors to monitor how blood vessels during embryonic develop- concerned with the pull and push form over time in a live ment, in healing wounds, (Figure 5). and in reproduction. Vessel of outside tissues, with blood- growth involves at least pressure and blood-circulation, An early embryo is small three processes: and with the interchange of sub- enough for its cells to get the • is the stances through the wall.” formation of blood ves- necessary oxygen and nutrients sels from embryonic or through diffusion. As it grows The metamorphosis of a lar- bone-marrow-derived larger, too large for diffusion to circulating endothelial val tadpole into an adult frog precursor cells or other be effective, a circulatory system requires reorganization of many cell types, usually dur- begins to form, assembling the ing embryonic develop- body systems, including the cir- plumbing network required to ment. culatory system. Any vertebrate transport what needs to be moved • Angiogenesis (some- animal, be it a frog or a human, times called neovascu- throughout the body. Embryonic larization) is the forma- undergoes massive changes in the endothelial cells lay down a net- tion of new vessels, process of changing from a fertil- work of capillaries. Over time, usually capillaries, by sprouting from existing ized egg to an adult, a process the embryonic vascular system vessels. Angiogenesis is sprouts new capillaries where thought to be driven by needed and prunes capillaries low oxygen levels. • is blood away where they are not needed. vessel maturation by Vessels enlarge and mature, add- the addition of cell lay- ing layers of cells to become ers to make a larger vessel. Arteriogenesis arteries and veins, supplying the is thought to be driven expanding organism with a corre- by mechanical factors, sponding expanding vasculature such as those Eliot Clark described in tad-

in a process called vasculogen- Three Ways to Build Blood Vessels pole tails. esis.

In a normal healthy adult, would not come to fruition until major changes in the vascular decades more of careful observa- system only occur in specific tion by scientists. Figure 5 – Zebrafish: A number of ani- circumstances, such as during the mal models have been used to study female reproductive cycle, or in angiogenesis in normal physiology the case of tissue injury, when Watching through and disease. Recently, scientists have Windows inserted genes into zebrafish which new blood vessels are needed to cause blood vessels to fluoresce green, replace damaged ones. Changes At the University of allowing scientists to observe forma- can also occur when the demand Pennsylvania, Eliot Clark, who tion of new blood vessels and changes for oxygen increases (with ath- had so painstakingly described in response to stimuli in live . Figure courtesy of Drs. Yung-Shu Kuan letic training, for example) or the the capillaries in tadpole tails and Marnie Halpern. availability of oxygen decreases in 1918, worked side-by-side in (such as at high altitude). These his lab with his wife, Eleanor, that has been studied extensively changes are known as angiogene- an “unpaid volunteer.” One day, throughout the last century. In sis, and our understanding of how Eleanor accidentally pierced her a modern version of the tadpole this process works and how we finger with a glass tube as fine tail, investigators have recently could exploit it to treat disease as a strand of hair. After several

Breakthroughs in Bioscience 4 a workhorse in the scientific community for decades. It was even featured in a 1939 issue of Time Magazine, which highlight- ed the Clark’s important work on vascular development. Later adapted to the skin on the backs of mice and to the cheek pouches of hamsters, the chamber created a window on the inner workings of living animals and has been used to study a variety of pro- cesses, such as and tissue transplantation, and to see how chemical and physical treat- Figure 6 – Rabbits: Eliot and Eleanor Clark (not pictured) from the University of ments affect these processes. Pennsylvania developed a method to study blood vessel development in the rabbit’s ear. Although a 1939 Time Magazine article described the experiments in a tongue-in- The Sandison-Clark chamber cheek fashion - “the rabbits are placid and happy, wear warm grey flannel pajamas, allowed up-close visualization take vacations in Europe, occasionally feast on ice cream and cake” - this procedure allowed scientists to study angiogenesis in living mammals without the need for major of the healing process and of the surgery or heavy sedation. Although rabbits and other animals remain critical models formation of new blood vessels in modern biomedical research, like the Clarks, today’s researchers continually seek as tissue refilled the space in the new methods to refine experiments, reduce the number of animals used, and replace chamber. The process begins as animal models with alternative methods. Photo credit: Science Photo Library bleeding stops and a clot forms. days, her finger swelled up, and Infiltrating cells replace the clot they removed the glass. Being with a sort of temporary filler the meticulous scientists they called “.” New were, the Clarks looked inside blood vessels also appear in the the glass tube with a microscope wound at this time, sprouting and saw capillaries growing off of the remaining uninjured there. This gave them the idea to vessels and reestablishing blood make a “window” on the vascular flow so that healing can con- system of a rabbit’s ear. In 1924, tinue. As the wound continues to they, along with Clark’s student, heal, new cells enter and produce J. Calvin Sandison, designed stronger, more permanent tis- what was thereafter to be called sue. Scientists were now able to the Sandison-Clark chamber, in observe, and begin to understand, which a small hole is punched in the formation of new blood ves- the ear of a rabbit, and the area is Figure 7 – John Hunter: An 18th century sels following damage or injury: placed between two transparent Scottish surgeon and naturalist, John angiogenesis. plates. The tissue grows back to Hunter was one of the foremost scien- fill the area, which can then be tists of his day and an early advocate observed by placing the chamber, of the scientific method. He was the Dynamic Plumbing: first person to coin the term “angio- still attached to the living rabbit’s genesis” and conducted a number of Angiogenesis and ear, under a microscope (Figure 6). important studies looking at the growth Adaptation of new vasculature in the antlers of The technique was widely deer. Source: National Portrait Gallery, Healing an injured part of the adopted and the chamber became London. body requires rebuilding the

Breakthroughs in Bioscience 5 vascular system, starting from not have been the first to observe cells. Extensive physical training scratch. But the body can also collateral circulation, but he may can promote the growth of collat- remodel its plumbing, in other have been the first to recognize eral vessels in the skeletal mus- words undergo angiogenesis, in its clinical significance. When cles, heart, and parts of the brain. response to changing needs. It is Harvey first described the circu- The increased demand for oxy- especially responsive to oxygen lation of blood, he described the gen may be a trigger for vessel (or the lack thereof). Reduced heart as a pump that circulated growth. In addition, mechanical levels of oxygen (hypoxia) or blood throughout the body. But forces are generated by increased reduced blood flow () the cells of the heart are just as blood flow in collaterals when results in reduced oxygen avail- reliant on blood as any other cell flow is restricted elsewhere and ability for tissues. The noted in the body. Lack of oxygen can this may also contribute to the Scottish physician, John Hunter damage the cells of the heart growth of collaterals. Collateral (Figure 7) was an early investiga- muscle, and they may function growth is the body’s clever way tor in this field, and conducted a ineffectively, or even die. If the of using angiogenesis to adapt classic experiment involved the pump fails for lack of oxygen, to new challenges. But scientists antlers of male fallow deer. the blood doesn’t circulate, and were soon to discover that our the cells in the rest of the body body’s tissues were not the only In July 1785, Hunter tied off will quickly fail; brain cells can ones using angiogenesis for sur- the artery that supplied one of only live a few minutes without vival. a deer’s antlers. The affected blood. antler became cooler, indicating that it was not getting enough The heart has a rich supply of blood. Hunter expected the ant- blood vessels to keep the heart ler, deprived of blood, to die muscle supplied with oxygen. and fall off. In a week or two, Not surprisingly, the heart has however, the antler warmed up a backup, or alternate routes, in again. Thinking his procedure case the main supply is inter- may have failed, he investigated rupted. In describing this wide- further. The artery he had tied off spread cardiac collateral circula- was still blocked, but around that tion, Charles L. Hudson, Alan blockage he observed a network R. Moritz, and Joseph T. Wearn of new vessels that had grown, suggested, in 1932, that collater- enlarged, and connected with als are “probably of significance other vessels to supply the ant- in compensating for sclerosis ler. This is now called collateral [thickening or hardening] of circulation. Hunter applied his the large trunks of the coronary findings to vascular surgery in arteries.” Indeed, animal experi- humans, devising a groundbreak- ments and human postmortems Figure 8 – : A pioneering ing procedure to treat aneurysms have demonstrated that when scientist who proposed targeting angio- in leg arteries, thus avoiding the coronary vessels are blocked, genesis as an approach for cancer ther- apy, Folkman first became interested in need to amputate. existing collateral vessels enlarge medicine when accompanying his father, and additional collaterals form. who was a rabbi, on visits to patients in Blood vessels are not merely the hospital. Folkman strongly believed pipes through which blood flows. When the demand for oxygen in angiogenesis as a unifying concept They are dynamic and able to increases, as with prolonged, in developing new disease therapies, a adapt to changing conditions. intense athletic training, new vision which is being realized with an array of angiogenesis-related drugs on When one route is blocked, alter- capillaries can form to deliver the market. Courtesy of the Children’s nate routes can form. Hunter may more blood, and more oxygen, to Hospital, Boston.

Breakthroughs in Bioscience 6 Blood and Tumors This was not an entirely novel During his stint in the navy, observation. As early as 1865, Judah Folkman and his col- In 1960, during his surgi- German physician Rudolf league David Long encased cal residency at Massachusetts substances within a synthetic Virchow, often called “The General Hospital in Boston, silicone rubber polymer (a very Father of Pathology,” observed large molecule composed of Judah Folkman (Figure 8) was that tumors were filled with numerous repeated subunits). drafted by the military. While blood vessels. In 1913, James When this was implanted serving his two-year stint in the into an animal, the substance Murphy placed rat tumor cells navy, Folkman worked at the leached out of the polymer, onto the membranes of develop- allowing slow, sustained deliv- Naval Institute ing chick embryos and noted ery into the tissue. Twenty in Bethesda, Maryland. He and that “numerous dilated vessels years later, with the participa- NYU pathologist Fred Becker tion of Sheldon Segal of the are seen coursing through the were assigned a project to come Rockefeller Foundation’s membrane and penetrating the Population Council, this tech- up with a cell-free blood substi- semitranslucent grayish tissue nology was used in the highly tute for transfusing into patients successful implantable contra- of the tumor itself.” A quarter when fresh blood was not avail- ceptive Norplant®. of a century later, Gordon Ide able. The idea was to dry hemo- Later, while studying angio- used the Sandison-Clark rabbit globin, the oxygen-carrying pro- genesis at Harvard, Folkman ear chambers to study the vas- needed a way to let suspected tein in red blood cells, so that it cular reaction to tumor cells and angiogenic factors leach could be reconstituted and keep proposed that tumors need new slowly into the corneas of his a patient’s cells alive until fresh experimental animals. The blood vessels to provide them blood could be obtained. silicone rubber he had used with the oxygen and nutrients previously had worked with

Sustained Release Polymers Folkman and Becker infused small molecules, but was they needed for growth. In 1941, not useful with larger ones, thyroid glands from dogs with Harry Greene transplanted rabbit like proteins. Folkman asked various solutions to keep the tumors into the eyes of guinea Robert Langer, an engineer organs alive outside the body. pigs, noting that “the tumors from MIT who was working as a post-doc in his lab, to design Their system could keep the obtained a blood supply from the a system to allow proteins to thyroid cells alive, but to deter- foreign host.” Glenn Algire and be released slowly, and Langer mine whether the system would his colleagues at the National devised a method of encasing allow cells to grow—instead of the experimental proteins in Cancer Institute adapted the rab- polymers that allowed them to merely surviving— they trans- bit ear window to the skin on be released over a long period ferred mouse tumor cells into the the backs of mice in 1945 and of time. They published a glands, cells they knew could suggested that “the change in description of the procedure in multiply rapidly. The tumors Nature in 1976. the tumor cell that enables it to grew, but only to the size of a Langer saw the potential for evoke capillary proliferation is the sustained release of drugs pin head. If the same tumors the only change necessary to in other applications and went were implanted into live mice, give the tumor cell its increased on to devote his career to they grew like wildfire. When autonomy of growth relative to developing new methods to Folkman removed the tumors and control the release of drugs. the normal cell from which it He was a pioneer in the devel- examined them, he noted that arose.” (Figure 9) opment of transdermal patches, the tumors that had grown were which are now used to deliver filled with blood vessels, while Although Folkman wasn’t such diverse substances as the tiny tumors were not. This the first to note the connection for smoking cessa- planted the seed of an idea into between tumors and vascular- tion, estrogen for menopause ity, he was the first to expand symptoms, and nitroglycerine Folkman’s brain: tumor growth for angina. depended on the growth of blood the idea further and propose a vessels. clinical application. Just as small

Breakthroughs in Bioscience 7 A separated the proteins by size Small localized tumor Tumor that can grow and spread into a series of test tubes. He Angiogenesis injected the fluid from each tube under the skin of rats to see if it induced blood vessel growth in the skin in order to find which tube contained the mysterious factor. The factor itself was not Blood vessel purified or characterized in any detail, but because of its ability Signaling to induce blood vessel growth, molecule Folkman dubbed it “tumor angio- genesis factor,” or TAF. B Figure 9 – Tumor angiogenesis: Tumor angiogenesis refers to the growth of The identification of TAF—and new blood vessels that infiltrate cancer- the discovery that tumors require ous tumors, supplying the tumor with a new blood supply to grow big- nutrients and oxygen. Angiogenesis occurs in response to the tumor sending ger than a pin head—prompted out signals to the tissues surrounding Folkman to hypothesize that them, which triggers blood vessel pro- interference with angiogenesis, liferation (A). Blood supply is impor- or with TAF in particular, might tant to tumor growth and metastasis (spread), and tumors are closely associ- rob a tumor of its blood supply, ated with their blood supply, as seen in and thus inhibit its growth. He this computer stimulation (B). Image proposed anti-angiogenesis as credit: National Cancer Institute, Corporate Press, and Science Photo a novel treatment for cancer in Library a talk in October 1971. A tran- script was published in the New England Journal of Medicine a organisms can survive without a Harvard Medical School, adapted few weeks later. vascular system by exchanging the Sandison-Clark rabbit ear materials with the outside envi- chamber to the cheek pouches His hypothesis was met with ronment by diffusion, Folkman of hamsters. By placing a mem- indifference, skepticism, and reasoned that the tumors were brane between the tumor and even ridicule. only able to grow to a small the tissue, they showed that the Despite a lack of support from size without a vascular system. tumor produced a factor that his peers—and funding agen- He suspected that the tumors could pass through the membrane cies—Folkman persisted with his did something to encourage the to promote angiogenesis on the experiments. He placed tumor growth of the blood vessels they other side. Direct contact wasn’t cells in a lab dish, where they needed, but he had to do more required; the factor could diffuse grew unrestricted when lying experiments to confirm his spec- from the tumor to the vessels it flat against the bottom, bathed in ulation. After his service to the affected. nutritive medium. When the cells military ended, Folkman returned Folkman set about trying to were grown in solid medium, in to Massachusetts General identify that diffusible factor. three dimensions, they only grew Hospital and continued his He and his coworkers ground to spheroids of about 3 or 4 mm research. Meanwhile, two groups up rat tumors and made a crude in diameter--about a million cells. of investigators, one at Chicago preparation of its proteins, which Folkman hypothesized that that Medical School and another at he passed over a column that was the limit beyond which cells

Breakthroughs in Bioscience 8 could obtain the nutrients they Angiogenic factors Angiogenesis inhibitors needed through simple (promote angiogenesis) (interfere with angiogenesis) diffusion—without a vascular • Basic fibroblast growth • system. He also looked to the factor (bFGF) • eye, and its unusual blood sup- • Acidic fibroblast growth • ply. Folkman and a post-doctoral factor (aFGF) • Platelet factor 4 fellow, Michael Gimbrone, found • Vascular endothelial growth • Thrombospondin that tumors placed near the iris factor (VEGF) • Tissue inhibitor of metallo- • proteinase (TIMP) 1, 2, and 3 of a rabbit’s eye, where there • Epidermal • Troponin 1 was a rich blood supply, grew • 8 • Angiopoeitin-2 quickly and to quite a large size. • Granulocyte colony- In contrast, tumors placed in the stimulating factor cornea, where there were fewer • blood vessels, did not die, but • Platelet-derived endothelial failed to grow to a size bigger growth factor than a millimeter or so. All of the • Tumor necrosis factor alpha (TNF-a) evidence seemed to confirm that angiogenesis was important to Table 2 – Factors that stimulate or inhibit angiogenesis: A number of naturally-occur- tumor growth. But how did this ring factors have been identified that either promote or inhibit growth of new blood process work? What were the vessels. (Note: List is not comprehensive.) factors involved? And how could factors, called acidic and basic of vascular endothelial cells. scientists use this information to fibroblast growth factors (aFGF In 1989, while working in the halt the growth of cancer cells? and bFGF), were first isolated department of cardiovascular from pituitary glands and brains. research at , Ferrara The Search for Factors: By the mid-1980s, they had been purified the protein and cloned purified, their genetic sequences the gene, naming its product Alphabet Soup determined, and the genes were vascular endothelial growth fac- In the 1970s, Michael Gimbrone cloned, that is, their genetic tor—VEGF (pronounced VEJ- came up with a way to grow sequences were inserted into bac- eff). Further characterization vascular endothelial cells in teria so that large quantities of revealed that VEGF was identical lab dishes, a feat that was once the proteins could be produced in to Dvorak’s VPF. In fact, in the thought impossible. This particu- the lab for further study. early days, many of the same fac- lar advance expedited the search At Beth Israel Hospital in tors were given different names for angiogenic factors, reducing Boston, in 1983, Harold Dvorak because investigators isolated the need for experiments using isolated a factor that made it them from different tissues or live animals or chick embryos. easier for certain proteins to measured different activities, The advent of molecular biol- cross the vascular endothelium such as the abilities of VPF/ ogy and other technical advances in such tissues as skin, lungs, VEGF to both stimulate vascular allowed the identification, iso- muscles, and the retina. Dvorak endothelium and make it more lation, and characterization of called it vascular permeability permeable. numerous angiogenic factors over factor (VPF). Meanwhile, at the It soon became clear that some the next few decades. (Table 2) University of California, San factors, like VEGF, have multiple Some factors were isolated Francisco, postdoctoral fellow functions, and that many known from tumors, but others were discovered factors also had activities that isolated from normal tissues. a novel growth factor activity affected angiogenesis (Figure Two angiogenesis-promoting that stimulated the proliferation 10). Other multifunctional growth

Breakthroughs in Bioscience 9 Figure 10 – How angiogenic factors affect angiogen- esis: Tumors release angiogenic (promoting blood vessel growth) factors, such as vascular endothelial Tumor factor (VEGF) or basic (bFGF). These interact with receptors on endothelial cells, setting off a series of events that lead to new growth of blood vessels. Endothelial cells release which degrade the proteins and complex sugars that are found in the matrix VEGF between cells in the surrounding tissues. This deg- (or bFGF) radation gives the endothelial cells room to migrate and multiply (proliferate). Over time they will begin to self-organize into hollow tubes and then con- tinue to grow into a mature, new network of blood vessels. Adapted from the National Cancer Institute, National Institutes of Health by Corporate Press. Endothelial cell factors with angiogenic proper- ties include epidermal growth Secretes enzymes that factor (EGF), tumor necrosis digests the materials factor (TNF), platelet-derived between cells, allowing for endothelial cell division growth factor (PDGF), and and migration. angiogenin.

Some multifunctional factors Endothelial cell have activities that interfere proliferation with angiogenesis. , a protein released by the immune system, for example, was first identified as an inhibitor of virus growth in cells. Bruce Zetter, a member of the Folkman lab, showed that one kind of interfer- Endothelial cells organize into hollow tubes that on, interferon-a, interferes with eventually form a network the proliferation and migration of new blood vessels. of endothelial cells, which is an important step in the formation of anti-angiogenicTumor properties.cell new capillaries. In other words, School of Medicine found herself listening to one of Folkman’s interferon has anti-angiogenic After reading DrugsBouck’s can stop thrombo the - talks in 1987. (Later, Bouck spondin paper, Folkmanproduction offormed function in addition to its antivi- angiogenic growth ral function. would reveal that she ended up a new hypothesis tofactors. explain a in Folkman’s lecture VEGFbecause she Ex. Interferon-a (or bFGF) vexing problem for cancer sur- Switch Off, Switch On had worn a new pair of shoes geons—removal of some tumors to the conferenceDrugs and can needed block causes tumors in other sites of Some naturally-occurring the receptors of Drugs can bind or interfere a place to sit downprevent to cells rest from her the body towith grow growth more factors. rapidly. factors—like interferon-a— Ex. Avastin, Endostatin, aching feet!) Shemaking was receptors. inspired inhibit the growth of new blood Ex. Cetuximab Folkman hypothesizedTNP 470, Thalidoamide that cells vessels. Another rich source of by what she had seen and sub- from the main tumor metasta- inhibitory factors turned out to sequently went onEndothelial to show that cell size, or spread, to other parts be the tumors themselves. By thrombospondin, a factor first of the body, but that the distant chance, Noël Bouck, a researcher isolated from blood platelets, was tumors only growDrugs to can a interfere limited at Northwestern University also released by tumors and had size. The main withtumor degradation prevents of the cellular matrix. Ex. Marimastat, Neovastat Breakthroughs in Bioscience 10

Endothelial cell proliferation

Drugs can interfere with cell proliferation or growth of new blood vessels Ex. Inject Introduced in the 1950s in Europe, cancer cells was used to treat insomnia and morning sickness. Although not approved by the FDA, it was used widely in Europe and Canada until 1962, when it was associated with birth defects in at least 8,000 (and as many as 20,000) babies of women who had Let initial taken the drug while pregnant. The defects included tumor grow for missing digits, stunted arms and legs, and deformed several weeks internal organs (see figure). The drug was taken off the market in most countries. In the search for angiogenesis inhibitors, Robert D’Amato, who joined Folkman’s lab in 1992, decid- ed to take another look at thalidomide. D’Amato Remove found that the reason it caused birth defects was initial tumor that it was interfering with angiogenesis. Although it took some doing to get approval for this contro- versial drug associated in so many people’s minds with tragic birth defects, the first human trials began

New Use for a Notorious Drug in 2000. By 2006, thalidomide was approved by the FDA for the treatment of . Allow time for metastases to appear Angiostatin No injections treatment Thalidomide: Few metastases Many Metastases

Figure 11 – Angiogenesis inhibitors and metastasis: Michael O’Reilly, a postdoctoral Folkman set a new post-doc, fellow working with Judah Folkman, first isolated angiostatin, a naturally occurring Michael O’Reilly, to the task protein that inhibits angiogenesis. Angiostatin is produced by primary tumors and prevents the growth of metastases, or secondary tumors that occur when cancer of isolating more angiogenesis cells spread. Scientists have shown that if the primary tumor is removed, as shown inhibitors from tumors. O’Reilly in this diagram, metastasis may occur unless an inhibitor, such as angiostatin, is overcame some technical hurdles administered. This helped explain a problem that had baffled cancer surgeons: why and finally, after collecting 18 removal of a tumor seemed to promote cancer spread to other tissues. The pursuit of angiogenesis inhibitors is a major area of research in the quest for new cancer liters of urine from mice with treatments, and a number of angiogenesis inhibitors have already been approved tumors, he isolated an inhibitor, as cancer drugs. Adapted from the National Cancer Institute, National Institutes of which they called angiostatin Health, by Corporate Press. (Figure 11). A few years later, them from forming their own pro- and anti-angiogenic factors using a similar strategy, they vascular systems by producing determined whether angiogen- came up with another inhibitor, angiogenesis inhibitors. When esis was stimulated or inhibited. called endostatin. the main tumor is removed, that When the main tumor was pres- Not all inhibitors are found in inhibition is removed as well, ent, it switched angiogenesis off humans, and some of them were and the distant tumors grow in the other tumors, but once it discovered serendipitously. One larger. Folkman compared it to was removed, the distant tumors example was TNP-470. An inves- throwing a switch; the balance of switched angiogenesis on. tigator in Folkman’s lab, Don

Breakthroughs in Bioscience 11 Tumor cell

VEGF (or bFGF)

Receptor Endothelial cell

Secretes enzymes that digests the materials between cells, allowing for endothelial cell division and migration.

Endothelial cell proliferation

Endothelial cells organize into hollow tubes that eventually form a network of new blood vessels. Inhibitors have been synthesized in the laboratory, but also found Tumor cell in tree bark, garlic, ginseng, and

Drugs can stop the shark cartilage (see also thalido- production of mide sidebar). Today there are angiogenic growth factors. at least 300 known inhibitors, at VEGF Ex. Interferon-a least thirty of which are found (or bFGF) naturally in the body (endog-

Drugs can block enous inhibitors). the receptors of Drugs can bind or interfere prevent cells from with growth factors. making receptors. Ex. Avastin, Endostatin, Ex. Cetuximab TNP 470, Thalidoamide From Finding Factors to Drug Development Endothelial cell But how does it all fit together? With at least 20 different endog-

Drugs can interfere enous angiogenic growth factors with degradation of and at least 30 endogenous inhib- the cellular matrix. Ex. Marimastat, itors constantly in balance, what Neovastat is the signal that tips the scale and flips the angiogenic switch? Endothelial cell One important signal is oxygen, proliferation or a lack thereof. We have seen how reduced oxygen levels can promote blood vessel growth in skeletal and heart muscles. This also appears to be true in tumors. In 1992, two groups of scientists, Drugs can interfere one from Israel and one from with cell proliferation or Germany, published back-to- growth of new blood vessels back papers in the journal Nature Ex. Integrins showing that areas of a tumor with the lowest levels of oxygen Figure 12 – Drugs target different stages of angiogenesis: There are a number made high levels of VEGF. The of stages of angiogenesis that can be stopped by drugs to inhibit blood ves- sel growth associated with disease such as cancer or macular degeneration. tumors respond to hypoxia by Adapted from the National Cancer Institute, National Institutes of Health, by switching angiogenesis on. Corporate Press. Analysis of the mechanism of Ingber discovered a fungus con- in large batches to examine its hypoxia-induced angiogenesis taminating his cultures of epithe- potential to stimulate angiogen- has implicated several intermedi- lial cells. The cells near the fun- esis. The factor isolated from the ates that signal low oxygen and gus were all rounded up, much culture, fumagillin, was indeed result in the production of angio- different from the normally flat angiogenic, but unsuitable for use genic factors. Mechanical forces appearance of endothelial cells as a drug, so an altered synthetic associated with increased blood in culture. Highly reminiscent of form called TNP-470 was syn- flow, such as those described by thesized (and later adapted into a Alexander Fleming’s serendipi- Eliot Clark in his observations drug called caplostatin). tous discovery of penicillin as a of the tadpole tail, also seem to fungal contaminant in 1929, the The search for angiogen- stimulate angiogenesis by caus- fungus was isolated and cultured esis inhibitors continues today. ing cells to produce angiogenic

Breakthroughs in Bioscience 12 factors, although the mechanism nounceable, commercial name, Into the Clinic and the is less well understood. Avastin, (Figure 13). Headlines The cellular and molecular Using an antibody to bind to By the 1990s, control of angio- processes that lead low oxygen and block a growth factor is only genesis was making its way into (or other signals) to stimulate one way to inhibit angiogenesis. the clinic. The first clinical trial vascular endothelial cells are Drugs have been developed that for cancer began in 1992, with being elucidated in greater detail, block early participants in the TNP-470, the precursor to caplo- revealing new targets for inter- angiogenesis process, such as statin that was inspired by a fun- vention. In addition to all the gal contaminant. Angiogenesis mTOR, and inhibit the produc- factors themselves, there are burst into the nation’s conscious- molecules that stimulate cells ness on Sunday, May 3rd, 1998, to make the factors, like mTOR when an article on the front page (mammalian target of rapamy- of the New York Times, pro- cin) and HIFs (hypoxia-inducible claimed, “HOPE IN THE LAB... transcription factors). There are A Cautious Awe Greets Drugs also the receptors on the endo- That Eradicate Tumors in Mice.” thelial cells that respond to the This was soon followed by cover factors, and the molecules within stories in Newsweek, Time, and the cells that take the signal from U.S. News and World Report the receptor and tell the endothe- (Figure 14). The press buzz made lial cell to start (or stop) making a cure for cancer seem imminent. more capillaries. The more we know about the mechanisms of angiogenesis and the participants Figure 13 – Avastin: , in the process, the more targets whose trade name is Avastin, was the first approved we have available for potential to treat cancer in the United States. It exploitation in drug development is a that specifi- (Figure 12). cally blocks vascular endothelial growth factor (VEGF), which is produced by Back at Genentech, Napoleone tumors to promote angiogenesis. Ferrara had been developing a drug to inhibit the actions of tion of growth factors. Other VEGF. He and his team made drugs block the growth factor a lab-produced version of anti- bodies, the proteins the immune receptors, or keep endothelial system secretes to protect against cells from making the recep- disease-causing microorgan- tors, so that growth factors have Figure 14 – Angiogenesis makes the isms (See the Breakthroughs in no way to exert their effect on headlines: In 1998, tremendous excite- ment was generated about the pros- Bioscience article on monoclo- the endothelial cell. Still others pects of controlling angiogenesis to nal antibodies). Ferrara made interfere with the function of the treat cancer after a New York Times antibodies that bind to VEGF growth factor receptors, keeping article describing Judah Folkman’s work and prevent it from signaling made a cure for cancer seem imminent. them from signaling the cell to Similar stories graced the covers of angiogenesis. That antibody, after tell it to grow, or inhibit multiple Time, Newsweek, and U.S. News and much testing, eventually became World Report. Folkman himself was the first angiogenesis inhibitor steps of the angiogenic process. more cautious in promoting his break- to be approved by the FDA for And for some drugs that inhibit through discoveries, warning that can- angiogenesis, the mechanism is cer was a complex disease and stating, treating human cancer, bevaci- “We never use the word ‘cure’ because zumab (or the more easily-pro- unknown. it is far away.” Used with permission.

Breakthroughs in Bioscience 13 “If you have cancer and you entered clinical trials as cancer of oxygen, decreasing the need are a mouse, we can take good treatments. Today, around one for new blood vessel formation. care of you,” cautioned Folkman. dozen antiangiogenic drugs are “Vascular mimicry” refers to the Translating laboratory findings in approved by the FDA to treat fact that vessels within tumors mice—no matter how dramatic— cancer (Table 3). may be lined with tumor cells, to clinically useful treatments is Research into antiangiogenic instead of endothelial cells, lim- a long road fraught with numer- therapies continues and even iting the effectiveness of drugs ous dead ends. Clinical trials for with encouraging results and suc- that interfere with endothelial cell safety and efficacy may yield cessful treatments, challenges disappointing results. function. Our understanding of remain. The biggest problem is the molecular events associated the potential for the develop- Despite the caveats of Folkman with angiogenesis is incomplete, and other researchers, the enthu- ment of resistance to antiangio- especially in the relationship siasm of the general public for genic drugs. in tumor between the mechanical and antiangiogenic therapy was cells may produce additional mirrored by the NIH. In 1999, growth factors, or increase their metabolic factors that promote Richard Klausner, head of the production of growth factors, angiogenesis. Research is also National Cancer Institute, made overcoming the antiangiogenic aimed at finding ways to affect antiangiogenic therapies of can- effects of the drugs. Other muta- angiogenesis using the body’s cer a national priority. In 1999 tions may increase tumor cells’ own, endogenous factors instead alone, 48 antiangiogenic drugs ability to survive in low levels of introducing foreign substances.

Inhibits or Promotes Generic Name Brand Name Approved to Treat Angiogenesis Metastatic colorectal cancer, lung Bevacizumab Avastin Inhibits cancer, advanced breast cancer, kidney cancer Becaplerman Regranex Promotes Ulcers caused by diabetes Cetuximab Erbitux Inhibits Head and neck Erlotinib Tarveca Inhibits , pancreatic cancer Everolimus Afinitor Inhibits Advanced kidney cancer Myelodisplastic syndrome, multiple Revlimid Inhibits myeloma Panitumumab Vectibix Inhibits Metastatic colorectal cancer Macugen Inhibits Wet macular degeneration Luncentis Inhibits Wet macular degeneration Sorafenib Nexavar Inhibits Kidney and Kidney cancer, gastrointestinal Sutent Inhibits stromal tumors Tensirolimus Torisel Inhibits Advanced kidney cancer Thalidomide Thalomid Inhibits Multiple myeloma

Table 3— FDA-Approved Drugs Based on Angiogenesis: A number of anti-angiogenic drugs, primarily aimed at treating cancer and eye disease, have been approved for use in the United States, as has one angiogenic drug for treatment of diabetic ulcers. Many more promising drugs related to angiogenesis are currently undergoing clinical trials for a variety of diseases, but it remains to be seen if they will prove effective.

Breakthroughs in Bioscience 14 Beyond Cancer idly demonstrated for a second hypoxia in the eye, which in turn phenomenon if one understands prompts the secretion of VEGF Cancer was not the only disease a priori that the two are con- (which may be Michaelson’s on the government’s angiogen- elusive “Factor X”). As has been esis radar. A few months after nected. Furthermore, when the shown for so many other diseases the New York Times article was mechanisms underlying different associated with angiogenesis, low published, NIH released a request diseases can be related in this for research proposals aimed at way, the development of thera- oxygen promotes new capillary translating angiogenesis research peutics for one disease could aid growth. In this case, the growth into clinical treatments for a vari- the development of therapeutics of capillaries is overzealous and ety of diseases, stating that “con- for others.” The search for factors the capillaries are abnormally trolling the angiogenic process affecting angiogenesis may have fragile, which ultimately results may prove effective as a treat- been started with cancer in mind, in retinal damage and vision loss. ment paradigm for a wide range but the benefits of that research Age-related macular degenera- of cardiovascular and pulmonary have far-reaching consequences. tion, too, has VEGF as a player diseases, for inhibiting tumor In 1948, Isaac Michaelson in disease promotion. In fact, one growth and metastasis, and for suggested that a diffusible fac- of the first antiangiogenic drugs, preventing and treating certain tor, which he called “Factor X,” Avastin, which blocks VEGF and eye diseases.” promoted the abnormal revas- was originally approved for can- Despite the prodigious output cularization associated with eye cer, is also effective against mac- of Folkman’s lab, he was not diseases like diabetic retinopathy. ular degeneration. Antiangiogenic the only investigator interested Half a century later, ophthal- treatments continue to be stud- in angiogenesis, nor was can- mologist Anthony Adamis, in ied. Today, there are two FDA- cer the only clinical application collaboration with investigators approved antiangiogenic drugs of experimental findings about including Jan Miller and Lloyd for eye diseases. Both of them angiogenesis. Folkman, himself, Paul Aiello, began exploring inhibit VEGF. knew this and proposed angio- the basis of abnormal capillary genesis as an “organizing princi- growth. Together, they showed Promoting Angiogenesis ple” for drug development, writ- that the vessels in the eyes of to Save Legs and Lives ing, in 2007, “the discovery of diabetics become clogged by the Encouraging angiogenesis is not a molecular mechanism for one exceptionally “sticky” cells flow- always a bad thing. While most phenomenon might be more rap- ing through them. That produces of the research on angiogenesis

A B

Figure 15 – Promoting angiogenesis for : As the Clarks discovered in the 1930s, angiogenesis is an important part of wound healing. Therapeutic angiogenesis, or the promotion of blood vessel growth to treat disease, is currently being used to treat chronic wounds (A), associated with diseases like diabetes or multiple sclerosis, in which prolongation of the wound may be due to abnormalities in vasculature. Treatment with angiogenic factors, like those found in Regranex, an angiogenesis-stimulating ointment, can lead to healing of chronic wounds and ulcers (B). Courtesy of the Angiogenesis Foundation.

Breakthroughs in Bioscience 15 has focused on inhibiting the pro- system. Patients with peripheral ness of breath, or even a heart cess in tumors and neovascular arterial disease have limited cir- attack. Collateral circulation can eye diseases, other investigators culation in the legs, which may compensate, but it may not be have been looking at it from be painful, and eventually require enough. One way to overcome the other direction. Therapeutic amputation. Since angiogenic this problem is by angioplasty, angiogenesis, or the promotion growth factors are involved in the surgery to open up the vessels. of angiogenesis to treat disease, development of collateral circula- Another is bypass surgery, where is also an active area of clinical tion, he decided that therapeutic vessels from other parts of the research. angiogenesis might be an effec- body are grafted into the heart to The process of wound healing, tive treatment for this insufficient replace the blocked vessels. But for example, involves the same blood flow. bypass surgery is invasive sur- pro-angiogenic factors as those He and post-doctoral fellow, gery that may not be appropriate used by tumors, including VEGF Satoshi Takeshita, performed or sufficient to increase the blood and FGF. In fact, Harold Dvorak experiments reminiscent of John supply to a satisfactory level. noted the similarities between Hunter’s deer antler experiment, Isner adapted his tumor angiogenesis and wound tying off an artery to block blood treatment to the heart. Between healing, calling tumors “wounds flow to the legs of rabbits. Before 1997 and 1999, Isner treated that do not heal,” meaning that tying off the artery, however, several dozen patients by inject- both tumors and healing wounds Isner and Takeshita injected the ing VEGF DNA into their . make VEGF, but the tissue in a angiogenic factor, FGF. The Ninety percent of the patients healed wound stops producing injection enhanced the forma- showed improvement in their VEGF, while a tumor does not. tion of collateral blood vessels. heart symptoms. More than 30 factors have been They repeated the experiment Although there was some con- identified as participating in the with VEGF, again resulting in troversy over Isner’s technique— wound healing process. increased formation of collateral and gene therapy in general—the circulation compared with rabbits When wound healing is inhib- idea of pro-angiogenic treatment injected with an inert placebo. ited, as often occurs in diabetics, of peripheral and coronary artery augmentation of the angiogenic Since growth factors lose activ- disease caught on. More clinical process helps promote wound ity shortly after being injected, trials were initiated, some using healing (Figure 15). In 1997, Isner looked to gene therapy. He growth factors and some using the FDA approved becaplermin injected the gene for VEGF into gene therapy. Clinical trials in (Regranex), an ointment contain- experimental animals with great therapeutic angiogenesis have ing a genetically-engineered form success. Eventually he used the also used immature endothelial of the angiogenic platelet-derived procedure on humans, and treated cells (endothelial progenitor cells growth factor (PDGF), for treat- over a hundred patients with poor and stem cells) to promote angio- ment of diabetic foot ulcers. In leg circulation over the course of genesis. Although it was antici- 1999 alone, ten clinical trials three years. pated that the cells themselves were conducted on therapeutic Encouraged by the improved would become part of the new angiogenesis for wound healing circulation in his patients’ legs, vasculature, the role of the intro- and similar research continues. Isner turned his attention to the duced cells seems to be one of a In the mid-1990s, Jeffrey Isner, heart. The arteries that supply growth factor factory, churning a cardiologists at Tufts University the heart with blood and oxygen out the factors the vessels that in Boston, began to think that can become blocked. When that need to sprout new capillaries therapeutic angiogenesis might happens, cells of the heart muscle and improve circulation of isch- be applied to the cardiovascular may die, producing pain, short- emic tissues.

Breakthroughs in Bioscience 16 More to be Done to improve blood flow to tissues clinical trials that may lead to that need more blood. new treatments for cardiovascular and disease. cancer are the two biggest killers Jeffrey Isner died suddenly of a in the developed world, and the heart attack in 2001. The cells of Judah Folkman, too, died sud- requirement for blood ties these his own heart, deprived of oxy- denly of an apparent heart attack two seemingly unrelated diseases gen, did not survive long enough in 2008, in the Airport together. Angiogenesis research for him to see his ideas about on his way to a meeting of the is providing new ways to deprive therapeutic angiogenesis expand Angiogenesis Foundation. At cancer cells of their blood and into the diverse assortment of the time of his death, there were over 1,000 laboratories studying angiogenesis worldwide, more Further Reading: than 50 angiogenesis inhibitors http://www.cancer.gov/cancertopics/understandingcancer/angiogenesis in clinical trials, and more than http://www.pbs.org/wgbh/nova/cancer/ a million patients being treated http://www.contemporarysurgery.com/uploadedFiles/CS1103_angiogenesis.pdf with antiangiogenic therapy. http://www.angio.org/ua.php While Folkman himself said, http://www.pbs.org/saf/1202/segments/1202-6.htm “Science isn’t one success after Dr. Folkman’s War: Angiogenesis and the Defeat of Cancer (Random House, 2001), another. It’s mostly one success by Robert Cooke in a desert of failure,” clearly Biographies: the work on angiogenesis by Jacqueline Jaeger Houtman, Ph.D. writes about biomedical science from Folkman and the scientists who Madison, Wisconsin. She enjoys writing for physicians, scientists, middle school students, came before and after can be and the general public. Dr. Houtman is the author of the book, The Reinvention of Thomas Edison, and has also written for The Dana Foundation, World Book, and scientific journals, counted as one such success. including Clinical and Experimental Allergy and Journal of NeuroVirology. She can be reached at via her website: http://www.jhoutman.com/index.html

Robert J. Tomanek, Ph.D. is a Professor of Anatomy and Cell Biology, within the Carver College of Medicine at the University of Iowa. Dr. Tomanek’s research focuses on two areas regarding the mechanisms regulating the formation of the coronary vasculature and its remodeling: the regulation of coronary vasculogenesis, angiogenesis, and arterio- genesis during development; and the role of heart rate reduction (via a specific sinoatrial node inhibitor, (Ivabradine) on the coronary circulation and ventricular function after myo- cardial infarction. He is an Associate Editor for the American Journal of Physiology (Heart and Circulatory) and has serves on numerous editorial boards, including Experimental and The Breakthroughs in Bioscience Clinical Cardiology, Experimental Biology and Medicine, and the Journal of Molecular and Cellular Cardiology. Dr. Tomanek is a Fellow of the American Physiological Society and series is a collection of illustrat- American Heart Association and has been active in the leadership of both the American Association of Anatomists and the American Physiological Society. ed articles that explain recent developments in basic biomedi- Joseph C. LaManna, Ph.D. is a Professor of Physiology and Biophysics, Neurology and Neuroscience at Case Western Reserve University School of Medicine. cal research and how they are Research conducted in his laboratory is concerned with energy demand, energy metabo- lism, and blood flow in the brain. The role of these mechanisms in the tissue response to important to society. Electronic pathological insults such as stroke, cardiac arrest and resuscitation, and hypoxia is being actively investigated. He has authored or co-authored over 200 research papers and review versions of the articles are avail- chapters. Dr. LaManna is on the Editorial Boards of the Journal of Applied Physiology, Journal of Cerebral Blood Flow and Metabolism, and Brain Research. He is an active able in html and pdf format at member of multiple scientific societies, including: the Society for Neuroscience; American Physiological Society; International Society for Oxygen Transport to Tissues AAAS; the Breakthroughs in Bioscience International Society of Cerebral Blood Flow and Metabolism; Association of Anatomy, Cell Biology and Neuroscience Chairs; American Association of Anatomists; and is Vice website at: President for Science Policy and President-Elect for the Federation of American Societies for Experimental Biology (FASEB). www.faseb.org

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