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Can cancer grow forever if supplied with unlimited resources?

Can cancer grow forever if supplied with unlimited resources?



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If somehow a human could give a tumor unlimited resources, would the cancer grow forever? It seems like it would until it gets so large that it physically affects vital organs. Is what would likely happen?


Yes. The very first cells used to study cancer are still around (HeLa Immortal Cells - Named for the subject Henrietta Lacks) and are basically immortal as long as they're fed.

As for tumors, whether cancerous or not they most definitely can continue to grow until they become a serious medical issue (WARNING: GRAPHIC - 3 Largest Tumors Recorded). One of the largest recorded tumors was 300lbs (~140kg) in a woman's abdomen that sprouted off of an ovary. They had to operate with her laying on her side, otherwise it would have crushed her abdomen and killed her.

Not all forms of cancer are immortal or produce large tumors (the 300lb tumor was benign), but it's definitely within the realm of plausibility.


Why Cancer and Inflammation?

Central to the development of cancer are genetic changes that endow these �ncer cells” with many of the hallmarks of cancer, such as self-sufficient growth and resistance to anti-growth and pro-death signals. However, while the genetic changes that occur within cancer cells themselves, such as activated oncogenes or dysfunctional tumor suppressors, are responsible for many aspects of cancer development, they are not sufficient. Tumor promotion and progression are dependent on ancillary processes provided by cells of the tumor environment but that are not necessarily cancerous themselves. Inflammation has long been associated with the development of cancer. This review will discuss the reflexive relationship between cancer and inflammation with particular focus on how considering the role of inflammation in physiologic processes such as the maintenance of tissue homeostasis and repair may provide a logical framework for understanding the connection between the inflammatory response and cancer.


10 Real Life Examples Of Exponential Growth

Have you noticed green coloured mold on your bread spoiling your breakfast in a few hours? When you leave bread out for a long time, discolouration on bread occurs which is popularly known as bread mold. This bread mold is a microorganism which grows when the bread is kept at normal room temperature. The bread mold grows at a surprisingly alarming rate. This growth at a fast pace is defined as “Exponential Growth.”

Exponential growth is the increase in number or size at a constantly growing rate. In exponential growth, a population’s per capita (per individual) growth rate stays the same regardless of the population size, making it grow faster and faster until it becomes large and the resources get limited.

Let us check the everyday examples of “Exponential Growth Rate.”

1. Microorganisms in Culture

During a pathology test in the hospital, a pathologist follows the concept of exponential growth to grow the microorganism extracted from the sample. Microbes grow at a fast rate when they are provided with unlimited resources and a suitable environment. It makes the study of the organism in question relatively easy and, hence, the disease/disorder is easier to detect.

2. Spoilage of Food

When we keep cooked or uncooked food at room or warm temperature, it begins to get spoiled after some time. Almost everyone has come across the green discolouration which ruins the food and spreads quite fast. Microorganisms require a warm temperature to grow and divide at an exponential rate.

3. Human Population

The human population is increasing exponentially. As of February 2019, the total population of the world exceeded 7.71 billion, and the numbers are amplifying day-by-day. However, in some areas, growth is slow or the population is on the verge of decline. China is the most populous country and India ranks second. It is, however, estimated that India will lead the world by 2030.

4. Compound Interest

Compound interest is the addition of interest to the principal amount of a loan or deposit, or in simpler words, interest on interest. Compound interest at a constant interest rate provides exponential growth to the capital.

5. Pandemics

Pandemics are the outbreak of a disease throughout a particular area. For instance, during the influenza pandemic of 1918, the rate of patients suffering from flu increased and, therefore, it was considered an exponential growth of the disease.

6. Ebola Epidemic

One of the most threatening epidemics that has ever happened in the world has been the “Ebola Epidemic.” It spread at such an alarming rate that the scientists declared it as exponential growth.” This is a disease outbreak that is advancing in an exponential fashion,” said Dr. David Nabarro, who was heading the U.N.’s effort against Ebola.

7. Invasive Species

Most of us might have heard about the world’s worst invasive weed- Water Hyacinth. They are generally grown for decorative purposes. Due to their exponential growth, they often end up clogging the rivers and blocking sunlight and oxygen to the organisms in the water. An invasive species is a species which is not native to a specific location and tends to spread to a degree believed to cause damage to the environment, human economy, or human health.

8. Fire

Most of us have seen forests turning into ashes in a couple of hours. It has been found that the area damaged in a fire has an exponential relationship with the duration of burning.

9. Cancer Cells

Cancer is one of the most dreadful diseases in the world. Millions of people have already died of cancer, and many more are suffering from it, and the worst note is that cancer cells divide exponentially, if not treated.

10. Smartphones Uptake and Sale

In today’s scenario, even a 7-year-old child is seen holding a smartphone. The sale of smartphones in so rapid that it has been considered an exponential sale.


Prostate Cancer Genes Behave Like Those in Embryo

Gene activity in prostate cancer is reminiscent of that in the developing fetal prostate, providing further evidence that all cancers are not equal, Johns Hopkins researchers report. The finding could help scientists investigate how to manipulate the genetic program to fight a disease whose biology remains poorly understood despite more than half a century of investigation.

Decades ago, researchers noticed that cancers often display many of the same "forever young" features seen in healthy embryonic organs during their early development: fast growth, evasion of aging and death, recruitment of blood vessels to grow more tissue, lots of movement and invasion of nearby tissue.

Though researchers noticed these similarities as far back as the 1920s, the sophisticated technology necessary to test the relationships between development and cancer didn't exist until recently, says David Berman, M.D., associate professor of pathology, oncology and urology at the Johns Hopkins School of Medicine.

In a new study published online this week in Oncogene, Berman and his team used new gene-profiling technology to compare the normally developing prostate in mice to human prostate cancers. The work took advantage of extensive existing knowledge about prostate development in mouse embryos.

Male mice develop prostate glands in response to androgens - male hormones that include testosterone - during day 17 of a 21-day gestation. An absence of androgen in female mice causes the cells in the same area to develop into a vagina and urethra, but females can grow prostates if they are artificially supplied with androgen.

To kick-start prostate development on a precisely timed schedule, the researchers gave pregnant mice androgen shots on day 16 after conception, sending male hormone circulating through the mothers' bloodstreams to their developing litters. A second group of pregnant mice were injected with an inactive solution for comparison.

Using mouse gene chips that catalog nearly every gene in the mouse genome, the researchers probed to see which genes were turned on in the urogenital areas of developing female mice six and 12 hours after they were exposed to androgen. They also compared normally developing females (not exposed to androgen) and males (which make their own androgen).

Their gene-profiling results showed that the pattern of activity of genes presumed to be turned on and off by androgen exposure changed dynamically over time. At six hours after injection, 693 genes responded to androgen, mostly by turning off. A little later on - at 12 hours - 177 genes responded, mostly by turning on. By 48 hours, on and off responses were approximately equal, with 829 genes responding to androgen.

"Our pet theory is that these developmental genes may be first turning off normal female development in response to androgens and then turning on prostate development," says Berman. "And when we looked closer at the nature of these genes we found that many are involved in cell survival, growth and movement, which are behaviors seen in cancer cells, so we probed further to see if these genes could be directly linked to prostate cancer."

By comparing the list of mouse genes to genes whose human counterparts are known to be involved in prostate cancers, the researchers found that many of these developmental genes appear to be turned on or off in prostate cancers, especially the more aggressive types and at critical transition points during cancer progression. Moreover, says Berman, the same genes that appear to cause cells to divide, move and change shape to form the prostate in a developing fetus also seem to be reactivated in prostate cancer cells, potentially causing them to divide, move and spread.

"We've identified the programs that form the prostate in the embryo and found them to be remarkably similar to those that form tumors in prostate cancer patients," says Berman. "Since prostate development is reproducible, genetically and pharmacologically tractable, and reflects the entire spectrum of human prostate cancer progression, this gives us a new roadmap for better understanding this particular cancer and identifying new prostate cancer-specific treatments."

These studies were funded by the Evensen Family, Passano, and Patrick C Walsh Prostate cancer foundations, and the National Institutes of Health.

Edward M. Schaeffer and Luigi Marchionni led the laboratory and analytic work. Other researchers who participated in this study include Zhenhua Huang, Brian Simons, Amanda Blackman, Wayne Yu and Giovanni Parmigiani.


Contents

Born in Sainte-Foy-lès-Lyon, Rhône, Carrel was raised in a devout Catholic family and was educated by Jesuits, though he had become an agnostic by the time he became a university student. [ citation needed ] He was a pioneer in transplantology and thoracic surgery. Alexis Carrel was also a member of learned societies in the U.S., Spain, Russia, Sweden, the Netherlands, Belgium, France, Vatican City, Germany, Italy and Greece and received honorary doctorates from Queen's University of Belfast, Princeton University, California, New York, Brown University and Columbia University.

In 1902, he was claimed to have witnessed the miraculous cure of Marie Bailly at Lourdes, made famous in part because she named Carrel as a witness of her cure. [7] After the notoriety surrounding the event, Carrel could not obtain a hospital appointment because of the pervasive anticlericalism in the French university system at the time. In 1903 he emigrated to Montreal, Canada, but soon relocated to Chicago, Illinois, to work for Hull Laboratory. While there he collaborated with American physician Charles Claude Guthrie in work on vascular suture and the transplantation of blood vessels and organs as well as the head, and Carrel was awarded the 1912 Nobel Prize in Physiology or Medicine for these efforts. [8]

In 1906 he joined the newly formed Rockefeller Institute of Medical Research in New York where he spent the rest of his career. [9] There he did significant work on tissue cultures with pathologist Montrose Thomas Burrows. In the 1930s, Carrel and Charles Lindbergh became close friends not only because of the years they worked together but also because they shared personal, political, and social views. Lindbergh initially sought out Carrel to see if his sister-in-law's heart, damaged by rheumatic fever, could be repaired. When Lindbergh saw the crudeness of Carrel's machinery, he offered to build new equipment for the scientist. Eventually they built the first perfusion pump, an invention instrumental to the development of organ transplantation and open heart surgery. Lindbergh considered Carrel his closest friend, and said he would preserve and promote Carrel's ideals after his death. [9]

Due to his close proximity with Jacques Doriot's fascist Parti Populaire Français (PPF) during the 1930s and his role in implementing eugenics policies during Vichy France, he was accused after the Liberation of collaboration, but died before the trial.

In his later life he returned to his Catholic roots. In 1939 he met with Trappist monk Alexis Presse on a recommendation. Although Carrel was skeptical about meeting with a priest, [10] Presse ended up having a profound influence on the rest of Carrel's life. [9] In 1942, he said "I believe in the existence of God, in the immortality of the soul, in Revelation and in all the Catholic Church teaches." He summoned Presse to administer the Catholic Sacraments on his death bed in November 1944. [10]

For much of his life, Carrel and his wife spent their summers on the Île Saint-Gildas [fr] , which they owned. After he and Lindbergh became close friends, Carrel persuaded him to also buy a neighboring island, the Ile Illiec, where the Lindberghs often resided in the late 1930s. [11]

Vascular suture Edit

Carrel was a young surgeon in 1894, when the French president Sadi Carnot was assassinated with a knife. Carnot bled to death due to severing of his portal vein, and surgeons who treated the president felt that the vein could not be successfully reconnected. [12] This left a deep impression on Carrel, and he set about developing new techniques for suturing blood vessels. The technique of "triangulation", using three stay-sutures as traction points in order to minimize damage to the vascular wall during suturing, was inspired by sewing lessons he took from an embroideress and is still used today. Julius Comroe wrote: "Between 1901 and 1910, Alexis Carrel, using experimental animals, performed every feat and developed every technique known to vascular surgery today." He had great success in reconnecting arteries and veins, and performing surgical grafts, and this led to his Nobel Prize in 1912. [13]

Wound antisepsis Edit

During World War I (1914–1918), Carrel and the English chemist Henry Drysdale Dakin developed the Carrel–Dakin method of treating wounds based on chlorine (Dakin's solution) which, preceding the development of antibiotics, was a major medical advance in the care of traumatic wounds. For this, Carrel was awarded the Légion d'honneur. Carrel also advocated the use of wound debridement (cutting away necrotic or otherwise damaged tissue) and irrigation of wounds. His method of wound irrigation involved flushing the tissues with a high volume of antiseptic fluid so that dirt and other contaminants would be washed away (this is known today as "mechanical irrigation.") The World War I era Rockefeller War Demonstration Hospital (United States Army Auxiliary Hospital No. 1) was created, in part, to promote the Carrel–Dakin method: [14]

"The war demonstration hospital of the Rockefeller Institute was planned as a school in which to teach military surgeons the principles of and art of applying the Carrel-Dakin treatment."

Organ transplants Edit

Carrel co-authored a book with pilot Charles A. Lindbergh, The Culture of Organs, and worked with Lindbergh in the mid-1930s to create the "perfusion pump," which allowed living organs to exist outside the body during surgery. The advance is said to have been a crucial step in the development of open-heart surgery and organ transplants, and to have laid the groundwork for the artificial heart, which became a reality decades later. [15] Some critics of Lindbergh claimed that Carrel overstated Lindbergh's role to gain media attention, [16] but other sources say Lindbergh played an important role in developing the device. [17] [18] Both Lindbergh and Carrel appeared on the cover of Time magazine on 13 June 1938.

Cellular senescence Edit

Carrel was also interested in the phenomenon of senescence, or aging. He claimed that all cells continued to grow indefinitely, and this became a dominant view in the early 20th century. [19] Carrel started an experiment on 17 January 1912, where he placed tissue cultured from an embryonic chicken heart in a stoppered Pyrex flask of his own design. [20] He maintained the living culture for over 20 years with regular supplies of nutrient. This was longer than a chicken's normal lifespan. The experiment, which was conducted at the Rockefeller Institute for Medical Research, attracted considerable popular and scientific attention. [21]

Carrel's experiment was never successfully replicated, and in the 1960s Leonard Hayflick and Paul Moorhead proposed that differentiated cells can undergo only a limited number of divisions before dying. This is known as the Hayflick limit, and is now a pillar of biology. [19]

L. Hayflick has shown that a cell has a limited number of divisions, equal to the so called "Hayflick's Limit." However, L. Franks and others (Loo et al. 1987 Nooden and Tompson 1995 Frolkis 1988a), have shown that the number of cell divisions can be considerably greater than that stipulated by the "Hayflick Limit", having practically no limit at all.

It is not certain how Carrel obtained his anomalous results. Leonard Hayflick suggests that the daily feeding of nutrient was continually introducing new living cells to the alleged immortal culture. [22] J. A. Witkowski has argued that, [23] while "immortal" strains of visibly mutated cells have been obtained by other experimenters, a more likely explanation is deliberate introduction of new cells into the culture, possibly without Carrel's knowledge. [a]

Honors Edit

In 1972, the Swedish Post Office honored Carrel with a stamp that was part of its Nobel stamp series. [24] In 1979, the lunar crater Carrel was named after him as a tribute to his scientific breakthroughs.

In February 2002, as part of celebrations of the 100th anniversary of Charles Lindbergh's birth, the Medical University of South Carolina at Charleston established the Lindbergh-Carrel Prize, given to major contributors to "development of perfusion and bioreactor technologies for organ preservation and growth". [25] Michael DeBakey and nine other scientists received the prize, a bronze statuette [26] created for the event by the Italian artist C. Zoli and named "Elisabeth" [27] after Elisabeth Morrow, sister of Lindbergh's wife Anne Morrow, who died from heart disease. It was in fact Lindbergh's disappointment that contemporary medical technology could not provide an artificial heart pump which would allow for heart surgery on her that led to Lindbergh's first contact with Carrel.

In 1902 Alexis Carrel went from being a skeptic of the visions and miracles reported at Lourdes to being a believer in spiritual cures after experiencing a healing of Marie Bailly that he could not explain. [10] The Catholic journal Le nouvelliste reported that she named him as the prime witness of her cure. Alexis Carrel refused to discount a supernatural explanation and steadfastly reiterated his beliefs, even writing the book The Voyage to Lourdes describing his experience, [28] although it was not published until four years after his death. This was a detriment to his career and reputation among his fellow doctors, and feeling he had no future in academic medicine in France, he emigrated to Canada with the intention of farming and raising cattle. After a brief period, he accepted an appointment at the University of Chicago and, [13] two years later, at the Rockefeller Institute of Medical Research.

In 1935, Carrel published a book titled L'Homme, cet inconnu (Man, the Unknown), [29] [ page needed ] which became a best-seller. In the book, he attempted to outline a comprehensive account of what is known and more importantly unknown of the human body and human life "in light of discoveries in biology, physics, and medicine", [13] to elucidate problems of the modern world, and to provide possible routes to a better life for human beings.

For Carrel, the fundamental problem was that:

[M]en cannot follow modern civilization along its present course, because they are degenerating. They have been fascinated by the beauty of the sciences of inert matter. They have not understood that their body and consciousness are subjected to natural laws, more obscure than, but as inexorable as, the laws of the sidereal world. Neither have they understood that they cannot transgress these laws without being punished. They must, therefore, learn the necessary relations of the cosmic universe, of their fellow men, and of their inner selves, and also those of their tissues and their mind. Indeed, man stands above all things. Should he degenerate, the beauty of civilization, and even the grandeur of the physical universe, would vanish. . Humanity's attention must turn from the machines of the world of inanimate matter to the body and the soul of man, to the organic and mental processes which have created the machines and the universe of Newton and Einstein. [29] [ page needed ] [30]

Carrel advocated, in part, that mankind could better itself by following the guidance of an elite group of intellectuals, and by incorporating eugenics into the social framework. He argued for an aristocracy springing from individuals of potential, writing:

We must single out the children who are endowed with high potentialities, and develop them as completely as possible. And in this manner give to the nation a non-hereditary aristocracy. Such children may be found in all classes of society, although distinguished men appear more frequently in distinguished families than in others. The descendants of the founders of American civilization may still possess the ancestral qualities. These qualities are generally hidden under the cloak of degeneration. But this degeneration is often superficial. It comes chiefly from education, idleness, lack of responsibility and moral discipline. The sons of very rich men, like those of criminals, should be removed while still infants from their natural surroundings. Thus separated from their family, they could manifest their hereditary strength. In the aristocratic families of Europe there are also individuals of great vitality. The issue of the Crusaders is by no means extinct. The laws of genetics indicate the probability that the legendary audacity and love of adventure can appear again in the lineage of the feudal lords. It is possible also that the offspring of the great criminals who had imagination, courage, and judgment, of the heroes of the French or Russian Revolutions, of the high-handed business men who live among us, might be excellent building stones for an enterprising minority. As we know, criminality is not hereditary if not united with feeble-mindedness or other mental or cerebral defects. High potentialities are rarely encountered in the sons of honest, intelligent, hard-working men who have had ill luck in their careers, who have failed in business or have muddled along all their lives in inferior positions. Or among peasants living on the same spot for centuries. However, from such people sometimes spring artists, poets, adventurers, saints. A brilliantly gifted and well-known New York family came from peasants who cultivated their farm in the south of France from the time of Charlemagne to that of Napoleon. [29] [ page needed ]

Carrel advocated for euthanasia for criminals, and the criminally insane, specifically endorsing the use of gassing:

(t)he conditioning of petty criminals with the whip, or some more scientific procedure, followed by a short stay in hospital, would probably suffice to insure order. Those who have murdered, robbed while armed with automatic pistol or machine gun, kidnapped children, despoiled the poor of their savings, misled the public in important matters, should be humanely and economically disposed of in small euthanasic institutions supplied with proper gasses. A similar treatment could be advantageously applied to the insane, guilty of criminal acts. [29] [ page needed ]

Otherwise he endorsed voluntary positive eugenics. He wrote:

We have mentioned that natural selection has not played its part for a long while. That many inferior individuals have been conserved through the efforts of hygiene and medicine. But we cannot prevent the reproduction of the weak when they are neither insane nor criminal. Or destroy sickly or defective children as we do the weaklings in a litter of puppies. The only way to obviate the disastrous predominance of the weak is to develop the strong. Our efforts to render normal the unfit are evidently useless. We should, then, turn our attention toward promoting the optimum growth of the fit. By making the strong still stronger, we could effectively help the weak For the herd always profits by the ideas and inventions of the elite. Instead of leveling organic and mental inequalities, we should amplify them and construct greater men. [29] [ page needed ]

The progress of the strong depends on the conditions of their development and the possibility left to parents of transmitting to their offspring the qualities which they have acquired in the course of their existence. Modern society must, therefore, allow to all a certain stability of life, a home, a garden, some friends. Children must be reared in contact with things which are the expression of the mind of their parents. It is imperative to stop the transformation of the farmer, the artisan, the artist, the professor, and the man of science into manual or intellectual proletarians, possessing nothing but their hands or their brains. The development of this proletariat will be the everlasting shame of industrial civilization. It has contributed to the disappearance of the family as a social unit, and to the weakening of intelligence and moral sense. It is destroying the remains of culture. All forms of the proletariat must be suppressed. Each individual should have the security and the stability required for the foundation of a family. Marriage must cease being only a temporary union. The union of man and woman, like that of the higher anthropoids, ought to last at least until the young have no further need of protection. The laws relating to education, and especially to that of girls, to marriage, and divorce should, above all, take into account the interest of children. Women should receive a higher education, not in order to become doctors, lawyers, or professors, but to rear their offspring to be valuable human beings. The free practice of eugenics could lead not only to the development of stronger individuals, but also of strains endowed with more endurance, intelligence, and courage. These strains should constitute an aristocracy, from which great men would probably appear. Modern society must promote, by all possible means, the formation of better human stock. No financial or moral rewards should be too great for those who, through the wisdom of their marriage, would engender geniuses. The complexity of our civilization is immense. No one can master all its mechanisms. However, these mechanisms have to be mastered. There is need today of men of larger mental and moral size, capable of accomplishing such a task. The establishment of a hereditary biological aristocracy through voluntary eugenics would be an important step toward the solution of our present problems. [29] [ page needed ]

Carrel's endorsement of euthanasia of the criminal and insane was published in the mid-1930s, prior to the implementation of death camps and gas chambers in Nazi Germany. In the 1936 German introduction of his book, at the publisher's request, he added the following praise of the Nazi regime which did not appear in the editions in other languages:

(t)he German government has taken energetic measures against the propagation of the defective, the mentally diseased, and the criminal. The ideal solution would be the suppression of each of these individuals as soon as he has proven himself to be dangerous. [31]

The Latvian translation of the book has been included in the 1951 list of books banned in the Soviet Union. [32]

In 1937, Carrel joined Jean Coutrot's Centre d'Etudes des Problèmes Humains - Coutrot's aim was to develop what he called an "economic humanism" through "collective thinking." In 1941, through connections to the cabinet of Vichy France president Philippe Pétain (specifically, French industrial physicians André Gros and Jacques Ménétrier) he went on to advocate for the creation of the French Foundation for the Study of Human Problems (Fondation Française pour l'Etude des Problèmes Humains which was created by decree of the Vichy regime in 1941, and where he served as "regent". [4]

The foundation was at the origin of the 11 October 1946, law, enacted by the Provisional Government of the French Republic (GPRF), which institutionalized the field of occupational medicine. It worked on demographics (Robert Gessain, Paul Vincent, Jean Bourgeois-Pichat), on economics, (François Perroux), on nutrition (Jean Sutter), on habitation (Jean Merlet) and on the first opinion polls (Jean Stoetzel). "The foundation was chartered as a public institution under the joint supervision of the ministries of finance and public health. It was given financial autonomy and a budget of forty million francs—roughly one franc per inhabitant—a true luxury considering the burdens imposed by the German Occupation on the nation's resources. By way of comparison, the whole Centre National de la Recherche Scientifique (CNRS) was given a budget of fifty million francs." [ This quote needs a citation ]

The Foundation made many positive accomplishments during its time. [9] It promoted the 16 December 1942 Act which established the prenuptial certificate, which was required before marriage, and was aimed at insuring the good health of the spouses, in particular in regard to sexually transmitted diseases (STD) and "life hygiene". The institute also established the livret scolaire [fr] [b] , which could be used to record students' grades in the French secondary schools, and thus classify and select them according to scholastic performance. [33]

According to Gwen Terrenoire, writing in Eugenics in France (1913–1941) : a review of research findings, "The foundation was a pluridisciplinary centre that employed around 300 researchers (mainly statisticians, psychologists, physicians) from the summer of 1942 to the end of the autumn of 1944. After the liberation of Paris, Carrel was suspended by the Minister of Health he died in November 1944, but the Foundation itself was "purged", only to reappear in a short time as the Institut national d'études démographiques (INED) that is still active." [34] Although Carrel himself was dead most members of his team did move to the INED, which was led by demographist Alfred Sauvy, who coined the expression "Third World". Others joined Robert Debré's "Institut national d'hygiène" (National Hygiene Institute), which later became the INSERM.


3 VIRTUAL CELL BIOLOGY LABS

The 10-week instructional spring 2020 quarter was changed to 8 weeks by SPU to accommodate 2 extra weeks of virtual classroom preparation. After researching virtual cell biology lab options, the instructor decided on eight labs to offer remotely (see Table 1). Each lab was created as a learning substitute to hands-on wet labs. Lab assignments included a prelab to prepare students for the virtual lab experience, a lab worksheet or protocol to guide students during the remote lab activity, and postlab questions to assess deeper student learning of the lab material. Both the instructor and a TA were available during each synchronous lab, as they would in an in-person lab, to help guide students during the lab. The instructor used Bloom's taxonomy learning outcomes to assess student learning. 10 Bloom's taxonomy contains six categories of learning outcomes, from lower-order skills that focus on knowledge and understanding, to higher-order skills that require deeper learning and cognitive processing. 10 While all Bloom's taxonomy learning outcome categories were used in our remote course, our remote cell biology course emphasized “Understand,” “Apply,” and “Analyze,” which taught students valuable scientific skills in a nontraditional learning environment (see Figure 1).

Our virtual lab experience focused on providing students a foundation of molecular and cellular biology techniques and skills to solve problems in cellular biology (see Table 1). The instructional materials included virtual simulations of lab activities, videos, real data files, as well as various scientific software and databases (see Table S1). Using these virtual tools, the instructor taught students lab theory, scientific methodology, and data analysis and critical thinking skills to solve scientific problems. More specifically, the instructor taught students: tissue culture techniques and calculations, various types of microscopy, various methodologies to study cell signaling during cancer, DNA sequencing and gene mutation identification, mitotic cell cycle stage identification using fluorescent microscopy, cell cycle analysis and flow cytometry, and the ability to recognize scientific data manipulation by image forensics. While students were not able to physically perform wet lab science, they learned important skills that can translate into future research settings (see Figure 1). For example, students learned various calculations involved in passaging and seeding cells for experiments. Students learned the detailed theory behind how various molecular and cellular biology techniques and equipment work. Students also learned bioinformatics, such as the use of NCBI BLAST and various biological software programs, which teach students software tools to analyze complex biological data. 11

The implementation of the scientific method is an important skill for students to learn and is often taught best in hands-on classroom lab experiences. While all our remote labs did not implement each step in the scientific method, some of the labs did include most or all the steps in the scientific method. For example, in the Labster “Confocal Microscopy Lab” simulation, students investigated a mysterious plant disease in a farm through simulated confocal microscopy methodology, performed data analysis of infected leaf samples, and then formed conclusions on what type of fungus the plant was infected with. Similarly, scientific methodology and set up are found in both Labster “Cell Signaling & Cancer” Lab simulations (see Table S1). For example, in the Labster “Signal Transduction” lab, the scientific problem students solved involved investigating the best method to treat cancer patients who have overactivation of vascular endothelial growth factor receptor (VEGFR). In this simulation, the experimental approach involved treating cancer tissue samples with inhibitors to VEGFR signaling and then using western blot to analyze the data. At the end of the lab, students formed conclusions on which drug candidate(s) were best suited to treat patients with overactive VEGF breast cancer. What is unique about the Labster simulations is they provide more than just a data interpretation exercise, which you would get in a lecture course. Students could virtually manipulate their experiments, from start to finish, in the simulations and almost sense what it is like being in a lab doing the experiments. Because of this, students experienced close to a real-life lab experience without being there in person.

The “Tissue Culture Basics” lab and the “Cell Calculation Lab” focused on tissue culture methods and calculations that are often used in tissue culture experiments. The “DNA Sequencing” lab (see Data S1) identified a problem for the students to solve, which was what specific DNA point mutation caused the Cdc14 proteins to change their distribution from filamentous networks to punctate spots in the nucleus. During this lab, the students learned the methodology to identify the point mutation by DNA sequencing and BLAST analysis using real sequencing data files. Ultimately, students were able to learn bioinformatics methodology through the analysis of real sequencing data, and they were able to form conclusions on where the point mutation was in the Cdc14B gene as well as what amino acid was changed in the mutant protein. In a lecture setting, students are often provided examples of final chromatograph data photos from DNA sequence results and then they may perform a short analysis on them. However, in our virtual lab, students learned how to navigate and open raw sequencing data files in a chromatograph viewer software. They then learned how to export the sequence data into BLAST, form alignments, and then analyze each DNA sequencing file to identify the DNA mutation in the Cdc14B gene. The “Stages of Mitosis” lab, provided freely by the Allen Institute (see Table S1), included all the steps in the scientific method. Students created a hypothesis regarding what mitotic cell stage(s) they expected to be most common. Next, they analyzed real cell image data using the Allen Institute's free web-imbedded cell viewer before discussing their results and forming conclusions. Additionally, the students learned how to use advanced flow cytometry software in the “Flow Cytometry and Cell Cycle Analysis” lab to quantify cell cycle stages (G1, S, G2, and M) and then formed conclusions from the data. While COVID-19 did not allow our cell biology students to perform in-person wet lab experiences, our remote labs allowed students to learn important bioinformatics and advanced biological software experimental tools, which they would not have had the opportunity to learn in our usual in-person cell biology lecture or lab course.


Don't Die, Stay Pretty.

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Introducing the ultrahuman makeover.

Judith Campisi, Calvin Harley, Cynthia Kenyon, and Gregory Stock are sitting onstage in a campus theater at UC Berkeley, looking a little shell-shocked. All four are big-time researchers studying various aspects of aging: Campisi is a cell biologist at Lawrence Berkeley National Laboratory, Harley is a cell biologist and chief scientific officer at Geron Corporation, Kenyon is a geneticist at UC San Francisco, and Stock directs the Program on Science, Technology, and Society at UCLA. They're not the types to brag about the implications of their work. But this event - Extro 4, the fourth confab of the Extropy Institute - is all about big-noise pronouncements, and the volume is drowning out the panel's scientific modesty.

The Extropians, of course, are techno-believers with boundless faith in science's power to amp up human potential. Extro 4 is devoted to their favorite topics: life extension, and the utopian future they believe will come about thanks to 21st-century advances in genetic engineering, biochemistry, and medical technology. A little later, the scientists will hear the Extropy Institute's founder, a chiseled, ponytailed philosophy PhD named Max More, confidently declare, "This is the fourth revolution in our history - the ultrahuman revolution." They'll also hear More's wife, an artist and bodybuilder named Natasha Vita-More, sketch out a future in which people will enjoy multiple sex organs, polymer skin that changes color like a mood ring, and virtual reality eyeball implants.

But right now the researchers are getting an earful from another Extropian, Robert Bradbury, a Harvard dropout and failed biotech entrepreneur. He provokes an awkward moment by addressing the panelists as fellow warriors in a crusade against anyone who doubts the possibility (or wisdom) of vastly increased human longevity.

"We have to deal with human naturalists," he says, "those people who think it is nonhuman to live 200 years, or the religious deathists, who have a significant amount of power by having the key to the Pearly Gates, so to speak, and the limits-to-growth camp, and, of course, the bureaucratic fearmongers like the Social Security Administration!" He looks at the scientists. "I realize most of the panel are not sociologists. Maybe Greg would like to comment."

Campisi tries to stifle a smirk. Harley's shoulders slump. Stock shifts in his chair and gets ready to say something. Here they sit, an all-star group, facing an organization founded by life-extension zealots who met at one of Timothy Leary's parties - and they've suddenly become "we." It's as if four Catholic bishops found themselves in a nude, sweaty scrum with a roomful of Larry Flynts.

MORE:
• Extropy Institute www.extropy.com
• The Life Extension Foundation www.lef.org
• Human Genome Sciences www.humangenomesciences.com
• Geron www.geron.com
• National Biocomputation Center biocomp.stanford.edu

But the scientists did show up, a visible acknowledgment that Extropian rhetoric isn't nearly as wild as it sounds. For years the research establishment has treated efforts to lengthen the maximum human life span as a kind of science porn. That's changing: In recent months, it has become obvious that many scientists and research corporations are taking longevity research seriously enough to make hefty investments in it.

Life extension remains a touchy topic, though. Few legitimate scientists will publicly advocate it government grants still don't flow to it. As enthusiastic amateurs, the Extropians can afford to be loud - but in the mainstream, reflexive condemnation is more often the rule. In his 1999 book on aging, Time of Our Lives, British gerontologist Tom Kirkwood dismisses as "contemptible" scientists who "tout their advances as heralding 200-year human life spans coming soon, or who condone journalists who hint at this."

"When people apply for funding to the National Institute on Aging, they are exceptionally careful not to bring up life-span extension," says Richard Miller, a University of Michigan gerontologist. "It is forbidden. They talk about specific diseases and preserving health and 'successful aging.' That is what's politically clever."

Uneasy though the Extro 4 panelists might be, the gap between the two sides is narrowing. The Extropians know it. The scientists know it. Gregory Stock especially seems to know it. Looking reluctant at first, he responds to Bradbury's monologue. To the Extropians' delight, he agrees with Bradbury. It's true, he says. Life extension is coming. In time the opposition will be outweighed by the sheer numbers of people willing to pay for a future of increased longevity.

And they will have something worth paying for. Because, Stock says, "we are at the point of remaking human biology."

Scientists have long regarded the human life span as relatively fixed. Currently, the maximum is 122 years, the age at which Frenchwoman Jeanne Calment, the longest-lived human for whom reliable records exist, died in 1997.

In the 20th century, doctors and researchers have focused mainly on expanding the average life expectancy, succeeding dramatically in the developed world - adding 30 years in the United States, for instance. Today, as a result of antibiotics, vaccines, public sanitation, and preventive medicine, so many centenarians are puttering around that Willard Scott would have to say happy birthday to about 200 a day just to keep up.

Until recently, it was assumed that these oldsters were simply edging closer to a set-in-stone life-span limit. But these days, a growing number of scientists agree that humans are poised for a breakthrough in longevity and what might be called "human repairability" - a new era that will not only raise the maximum age, but also deliver unimaginable new methods for preserving and even redesigning our own bodies. The scientific stigma is disappearing.

Just ask Michael Rose, a UC Irvine evolutionary biologist who has spent more than 10 years studying fruit-fly genetics, helping the flies more than double their previous life span. "I am now working on immortality," Rose says flatly. "It is an Einsteinian revolution compared with what we used to do."

Rose knows how jarring this sounds, even when he adds the caveat that immortality is generations away. "Twenty years ago the idea of postponing aging was weird and off-the-wall," he says. "Who gives a fuck what people consider flaky! If it's the truth, it's the truth, goddamn it, and I don't care if it is more than people want to hear."

Life extension is no longer shocking - researchers have achieved it regularly with lab animals, including mammals. In fact, it has occurred routinely since 1935, when rodents fed very-low-calorie diets started to outlive their chubby colleagues. Why this works remains unknown, but new research breakthroughs make it possible to consider aging seriously as a solvable problem. The solutions are not here yet, but they're close enough so a payoff is imaginable - and payoffs are what drive research. Rose argues that whoever harnesses life-extension technology first will reap the greatest economic reward in human history - not just on a Microsoft scale, but on the scale of the entire information age.

Already, a scientific land rush is under way. It focuses on three broad areas: the genetics of aging, techniques to immortalize cells and tissues, and exploitation of the basic modeling clay of our bodies - pluripotent stem cells.

The science underlying this scramble is becoming more solid every day. Life extension has been engineered in every lab animal that researchers have tinkered with: yeast, the nematode worm C. elegans, fruit flies, and mice. The techniques have varied. Michael Rose bred longer-living flies. Other researchers tweaked mice on the Weight Watchers plan, feeding them calorie-restricted diets that may have switched on still-mysterious genetic anti-aging mechanisms. (Calorie restriction is also being tried now with monkeys.) Geneticists have directly altered yeast and worms to make them live longer, and they're doing the same with mice.

The animals in all these experiments don't just live longer, they live better. Wild C. elegans look as tattered as a battle flag by the time they die. Cynthia Kenyon says the genetically altered worms she studies at UCSF look sleek and vibrant through middle age, a claim researchers using other species echo.

"My flies are superflies," Rose says of his insects. "My flies do more, for longer. They are having sex when other flies are long since dead."

Researchers don't agree on what specific mechanisms they've tapped into, or on what these may mean for humans. But what began as a tangle of possible longevity strategies is becoming a braided strand of knowledge about reproduction, energy, and stress.

Evolution plays the part of fickle lover to our bodies, or somas. It loves our somas, nurtures them, makes them strong in youth so we can pass on germ cells - our eggs and sperm - to produce another generation. Once we've accomplished this, evolution loses interest. If we live, fine. If we die, fine. The good news is that evolution doesn't require that we die, either. It doesn't care. It simply lets our bodies run down like a car with an empty tank.

Scientists are exploiting this fact from several angles. Food is one. A semistarved animal doesn't have sex on its mind: It focuses on survival. The soma may have a strategy for preserving itself through lean times so it can pass on germ cells later. Then, once sufficient food is available, the animal reproduces, passes on its germ cells, and the aging clock starts again.

This happens in the nematode C. elegans. When food is scarce, a very young worm can enter a kind of suspended animation, called dauer. It's still alive, it still can move, but it doesn't have much of a life. Once it encounters enough food, it snaps out of dauer, eats, and reproduces. In dauer, a worm can live for months. After coming out of dauer, it survives about two weeks.

But now there is a dauer bypass. Changes in just two C. elegans genes - daf-2, which Kenyon calls the "grim reaper" gene, and daf-16, the "fountain of youth" gene - doubled the lives of worms, even though they were well fed and not in dauer. That's roughly equivalent to humans living 200 years. What's so interesting about this approach is that daf-2 encodes a protein that looks very much like a receptor for human insulin and insulin growth-factor 1, both of which help control how the body metabolizes glucose, the basic form of cellular energy.

How we metabolize glucose may have a lot to do with why we grow old. When cells burn glucose, their smokestacks emit a form of pollution, rogue oxygen molecules called free radicals. These go bouncing through cells like Flubber in the china department at Harrods, crashing into cell parts and nicking chromosomes - so that when the DNA replicates, mistakes result. Over time, these rowdy molecules knock down the building. The cells age. Tissue function diminishes. The body ages. We die.

That process is called oxidative stress, and some researchers suggest it could be manipulated to increase longevity. When C. elegans worms are exposed to a variety of environmental stresses in incrementally larger doses, they live longer, possibly because the stress triggered genetically embedded protection mechanisms.

This tantalizing interconnectedness - that all the lab models share a significant number of genes with people, and that such small amounts of genetic meddling can so drastically lengthen a worm's life - has led Richard Miller, the University of Michigan gerontologist, to believe that "aging is a single, fairly tightly controlled process that has a relatively small number of genes timing it."

If Miller is right, researchers could someday develop small-molecule pharmaceuticals to manipulate human genes. Though the politics of life-extension drugs are snarled - at present, the FDA would never approve any drug developed for that purpose because proving its safety and effectiveness would be nearly impossible - some drugs may sneak in the back door.

Thomas Johnson, a University of Colorado geneticist who believes there are "no fixed upper limits to human longevity," suggests one possible scenario: "We will find some drugs that will be approved by the FDA because they prevent heart disease or Alzheimer's," he says, "and then we will discover - aha! - they also, by golly, make 80-year-olds look like 60-year-olds."

The steady drift of life-extension research toward the mainstream appears all the more likely because of the serious investment capital it's attracting. In 1997 Johnson, financed by several venture capital firms, started Genoplex, a privately held company that seeks to map quantitative trait loci, or QTLs, which he defines as groupings of genes that underlie complex traits like alcoholism, heart disease, and long life. Johnson's research, using DNA sensing and sequencing to target likely QTLs in mice in hopes of manipulating them, has drawn funding from the Ellison Medical Foundation, a nonprofit research outfit created in 1997 by Oracle CEO Larry Ellison.

Ellison also supports studies by other top longevity researchers, including Cynthia Kenyon and Judith Campisi, both of whom have predicted that dramatic life-span extension will become a reality in the 21st century. Ellison's PR manager says the foundation doesn't discuss its work, but longevity studies are obviously a high priority there. Ellison selected a big-league player, Richard Sprott, the former director of the Biology of Aging program at the National Institute on Aging, to administer up to $20 million annually ladled out to promising researchers.

Several marquee scientists are more outspoken than Ellison about how research today could lead to immortality tomorrow. Human Genome Sciences, based in Rockville, Maryland, is a $2 billion company that has partnered with pharmaceutical giant SmithKline Beecham to the tune of $125 million. It was founded by William Haseltine, a former Harvard biochemist and cancer researcher who helped decipher the structure of HIV. Haseltine claims to possess sequences for almost all human genes and to have a vast database of the products those genes make - including the chemical signals that direct stem cells. The company has three drugs in clinical trials, one of which involves injecting a gene into diseased muscle tissue to stimulate regrowth. This is the beginning of what Haseltine calls "regenerative medicine," a new era that, he says, will lead to "practical immortality - that is my concept." Haseltine doesn't mean in a few thousand years, either - more like 70 or 80. Eventually, he says, stem cells and genetics will give the human body "a transubstantiated future."

US Navy Commander Shaun Jones manages advanced biotech research programs for Darpa, which has a keen interest in technologies that can lead to new types of tissue or industrial-scale biological manufacturing of weapons.

Last spring Jones organized a meeting called NextMed 2 for SmithKline Beecham and the futurism-oriented Global Business Network. He believes seemingly diverse theories and innovations regarding aging are rapidly forming a grand, unified theory of human biology.

Whoever harnesses life-extension Technology first will reap the greatest reward in human history - wealth on the scale of the entire information age.

"Human longevity is an issue of convergence," he says. "Human genomics, C. elegans, plant genomics - you have an enormous number of these explorations without mastery. But all of it will converge." This situation, he says, created a consensus at NextMed 2. Which is? "That our generation," he says, "may be the last to have to accept death and taxes as inevitable."

As the chief scientific officer at Geron Corporation - one of the hottest biotech firms in the country - Calvin Harley is at the epicenter of this convergence. Harley has spent his entire adult life thinking about why people die. Now he occupies an office at Geron headquarters, a couple of buildings near Highway 101 in Menlo Park, California, where he continues to think about death and how to prevent it.

Harley is taking a holistic approach to the aging issue. Rather than focusing on individual aging genes or groups of genes, researchers at Geron are addressing other aging mechanisms, specifically telomeres and telomerase, the enzyme that keeps telomeres intact.

First proposed by a Russian theoretician in the 1970s, the telomere theory of cell aging postulates that these small structures of repeated DNA bases at the ends of chromosomes behave a bit like pencils in a sharpener. Each time a cell divides, the theory goes, a little more telomere data gets shaved off, until the telomeres become so short that the cell can no longer divide. Cells then become senescent - not quite dying, but not dividing either - simply idling and pouring toxic wastes into surrounding tissues. Telomeres act as an aging clock, the theory says, but telomerase can prevent them from shortening, thereby making cells immortal.

Geron's immediate commercial goal is to use telomere research in the detection and treatment of cancer. Most tumor cells, which divide indefinitely, produce telomerase. Locating telomerase-rich sites might be a way to locate developing cancers. Switching telomerase off through gene therapy might stop cancer from growing.

Harley is slight, fit, balding, intense, and reticent - a classic science guy. He works in labs stuffed to the ceiling with beakers, bottles, flasks, test tubes, chemicals, incubators, and gene sequencers. Among the sparse decorations in his office is a framed poster of Salvador Dalì's The Persistence of Memory. The artist's melting clocks, Harley explains, remind him of "the flexibility of time and possibly being able to manipulate the clock. It obviously has some significance to me and what I do in science."

Harley thinks that research is gaining on the secrets of aging, secrets he has wanted to unlock since his high school days in Ontario, Canada, when he puzzled over a paradox: How can an 80-year-old man use 80-year-old DNA in 80-year-old cells to father a baby whose cells are fresh as a daisy?

The answer, Harley thinks, lies in telomeres and telomerase. New research by Geron and others shows that telomerase can impart cell immortality - just as it does in an 80-year-old man's sperm, which produces telomerase naturally. And telomerase can do this in other cells - without, as some have feared, pushing those cells to become cancerous.

Geron's scientists believe that controlling the production of telomerase will prove useful not only in treating cancer, but also in slowing down human aging. Normal, noncancerous cells with a switched-on telomerase gene don't turn cancerous but instead divide properly. They don't go senescent, either, nor do they degrade surrounding tissue. Keep the telomerase going, and you keep your cells young, which keeps tissues young, which keeps people young.

"We are all born young," Harley says. "There is a capacity to have an immortal propagation of cells. The way we have evolved is to go from germline to germline, with our somas the dead-end carriers. But that is not inevitable."

In other words, people don't have to die.

Telomerase's ability to immortalize cells was a factor in Geron's decision last May to purchase Roslin Bio-Med - the people who brought us Dolly the sheep - thereby expanding into the other alluring branch of life-extension science: stem cells. Pluripotent stem cells may be the most promising avenue in longevity research because they can become any kind of tissue in the body. The ability to direct these cells' development and make them genetically identical to any patient's cells through cloning technology is leading to an era in which labs will custom-produce tissues and entire organs for transplantation - without fear of rejection.

The 80-year-old man in Harley's example can help create a baby not only because his sperm is kept immortal with telomerase but because a sperm cell's DNA gets reprogrammed after it joins an egg. The DNA is told to start over. The same process occurs in nuclear transfer, the technique that spawned Dolly.

In this arena, Geron faces serious competition from its departed founder, Michael West, president of a Worcester, Massachusetts, company called Advanced Cell Technology. Like Roslin Bio-Med, ACT is a cloning operation. It recently entered into a $10 million collaborative agreement with Genzyme Transgenics to use nuclear transfer to create a herd of cows that will produce human serum albumin, used to increase blood volume in surgery patients. ACT also hopes to manufacture transplantable human tissues. West thinks that with these and other emerging technologies, "depending on resources applied, there is no limit to the life span of human beings by 2099."

ACT has already repeated the early stages of the Dolly experiment on people by knitting a somatic cell from an adult human into an egg cell (in this case, a cow's) that had been emptied of its own genetic material. In that experiment, chemical signals hit the human DNA and told the cell to reset its clock. Had the resulting embryo been implanted into a woman's uterus, a human clone might have resulted.

Manufacturing pluripotent stem cells would have been that embryo's first order of business. It would have nestled the stem cells into a packet called a blastocyst. There, these cells would await chemical signals to switch genes on and off, dividing them into three branches: endoderm stems to form the gut organs mesoderm stems to form cartilage, bone, and muscle and ectoderm stems to form the nervous system. Other chemical signals would tell the DNA of these branched stems to produce more specific tissues - a liver, for example, rather than a pancreas. Some stem cells stop differentiating and enter a kind of on-deck circle to await further instruction. Hematopoietic stems, for instance, can respond to need by forming any of various types of blood cells.

In November 1998, a Geron team led by University of Wisconsin biologist James Thompson announced that it had derived and maintained human pluripotent stem cells in culture. In other words, it had produced the raw material for all types of human tissue.

"The real goal is to use a patient's own cells to make stem cells," says Harley. "That's the reason we acquired Roslin. They had the patents on this to create a fully competent embryo from an adult body cell. They reprogrammed it back to the embryonic state." From that state, Geron or ACT or some other firm could harvest pluripotent stem cells with a patient's own DNA from the blastocyst, grow them, and direct them to differentiate into any body tissue.

Pluripotent stem cells are immortal: They don't suffer telomere loss, and they constantly produce telomerase. But the moment stem cells begin to differentiate, they become mortal. Altering the gene for telomerase production - leaving it switched on - could make tissue cells immortal, too. Tissues that exactly matched their recipients' could be grown and transplanted, then stay young forever.


Lysins Unlimited: Phages’ Secret Weapon

It was 1917 when Felix d’Herelle, at the Institut Pasteur in Paris, first proposed using bacteriophages select or phages)—viruses that infect bacteria—as a therapy for human bacterial infections. Although used for decades in parts of Europe, notably Russia, Poland, and the Republic of Georgia, phage therapy is only permitted in the United States under the “compassionate use” umbrella—when there is nothing else available.

The rise of multidrug-resistant bacteria that defy traditional antibiotics has forced clinicians to seek alternative measures to curb deadly infections. Two cases made headlines in recent years. In 2016, the life of Thomas Patterson, PhD, a professor of psychiatry at the University of California, San Diego, was saved by phage therapy after he developed a deadly Acinetobacter baumannii infection. select The story is recounted in The Perfect Predator, the book that Patterson co-authored with his wife, epidemiologist Steffanie A. Strathdee, PhD.) Last year, the life of an English teenager was saved after she developed an infection following a lung transplant for cystic fibrosis.

Although phage therapy offers a promising way forward, other investigators want to take a more direct approach using only the active ingredient of the phage—the lysins—responsible for killing bacteria.

Roger Pomerantz, MD, president and CEO of Contrafect, compares lysins and phages to quinine and the fever tree. For many years, natural products were used in their entirety because the active agent had not been described. Upon isolating the active agent of the fever tree, or the foxglove plant select the source of digitalis union tree bark and flowers are no longer used. Understanding and isolating the active agent of phages removes the need to use the entire phage, or the “tree bark.”

Phage lysins work by degrading the bacterial cell wall, which is composed of the bacteria-specific molecule peptidoglycan. Different bacteria have different components and organizations of peptidoglycan in their cell walls different lysins are specific to these structures. Pathogens can have a slightly different composition than similar bacteria that are part of the normal flora. For example, the lysin for the gut pathogen Clostridium difficile will selectively kill C. difficile without harming other Clostridium present in the microbiota.

Around 2010, as awareness of the antibiotic resistance crisis was reaching a fever pitch, alternatives to antibiotics were being sought with a newfound urgency. One of the most promising set of candidates was under investigation in a laboratory on the Upper East Side of Manhattan, where researchers were discovering that lysins could be used clinically.

Night and day

Vincent A. Fischetti, PhD, the primary developer of the lysin technology, has been on the faculty at the Rockefeller University since 1973. He purified a phage lysin during his thesis work, using it to extract proteins from group A streptococci. Fast forward to the year 2000, Fischetti was, he recalls, “the right person at the right time.” He added lysin to the throats of mice that had been colonized with streptococcal bacteria. The bacteria died, and the idea to use lysins as a therapeutic was born. Fischetti obtained a broad patent, received two grants from the Defense Advanced Research Projects Agency select DARPA union and published a string of papers.

The differences between treating infections with phages and lysins, Fischetti explains, are “night and day.” Lysins are direct and kill instantly, and no resistance has been observed to date. Also, off-target effects are unlikely because peptidoglycan does not exist in mammalian tissue. Lysins are also very stable proteins—they can be frozen and lyophilized, and they are heat stable up to about 50°C.

When treated with lysins, a Gram-positive bacillus will externalize its cytoplasmic membrane before it ruptures and dies, as shown by this electron micrograph from the Rockefeller University lab of Vincent A. Fischetti, PhD. The bacillus, which maintains a high internal pressure, succumbs after lysins cut a few peptidoglycan bonds. “Boom, it’s going to explode!” exclaims Fischetti.

Moreover, lysins can infiltrate a biofilm, a bacterial community that normally offers bacteria extra protection from antibiotics. When biofilms are treated with antibiotics, only the organisms on the surface of the matrix are killed. In contrast, lysins dissolve biofilms from the top down. The bacteria burst open, revealing the next layer of the biofilm, making it vulnerable to further lysin exposure.

Graham Hatfull, PhD, a professor at the University of Pittsburgh specializing in phage biology, says there are vast numbers of different lysins, each with specific cell wall targets, creating a huge space for discovery and development. The lysins are relatively cheap and easy to produce. For several Gram-positive bacteria—which have only a single membrane located interior to the cell wall, giving lysins direct access to the peptidoglycan targets—good antibacterial activity has been shown in vitro. In short, Fischetti says, “They work.”

Getting lysins into patients

With the success of phage therapy in a couple of high-profile cases in recent years and the numerous advantages on paper of lysins as antibacterial drugs, one might ask: Why haven’t lysins received the same attention from the biopharma industry?

One reason is that the research did not leave Rockefeller University until about 10 years ago. That’s when Yonkers, NY-based biotech Contrafect approached Fischetti about licensing the technology to develop lysins as a therapeutic. Raymond Schuch, PhD, a research assistant professor in Fischetti’s lab at the time, joined Contrafect, where he is now vice president of research.

Schuch tells GEN that he made the move to Contrafect because it opened a whole new area of translational research that “we usually don’t think about in research laboratories.” Schuch continues: “We spent years identifying these lysins, defining their characteristics, showing that they confer therapeutic benefits in animals.” He wanted “to continue along the pathway of the development.”

In addition to lysins, Contrafect develops amurins, phage-encoded lytic antimicrobial peptides. Still in the discovery phase, these peptides have been shown to have in vitro activity against Gram-negative bacteria. The electron micrograph shows lysis of the Gram-negative bacterium Pseudomonas aeruginosa. select Lysis occurred over 20 minutes.) Treatments to counter Pseudomonas pathogens are much sought after because the pathogens cause multidrug-resistant nosocomial infections.

Over the past decade, the small company of 25 employees has taken the Staphylococcus aureus lysin Exebacase into the clinic, completing Phase I and Phase II of a trial. Contrafect is currently enrolling patients in Phase III. This is the first and only lysin to enter human clinical trials in the United States. The data showed that Exebacase, given in combination with antibiotics, improved clinical outcomes in patients with Staphylococcus aureus bacteremia, including endocarditis, when compared to antibiotics alone.

Although Exebacase is further down the clinical trial pipeline than any phage therapy in the United States, phage therapy has attracted all the public attention. Few have heard of lysins. “I don’t really know why,” remarks Fischetti. “That’s the problem.” One reason may be that lysins have not yet been approved for use in the compassionate care cases that tend to garner attention. When asked if there are any known disadvantages to using lysin over phage, Fischetti is adamant: “There are none.”

Path of least resistance

One of the major problems with phage therapy is the ability of bacteria to develop resistance, similar to the resistance that is rampant with antibiotics. In the recent cases where phages were used for compassionate care, the medical teams opted to use a cocktail approach, believing that one or even two phages could lose efficacy at some point due to the onset of bacterial resistance.

For example, in the case last year of the 15-year-old cystic fibrosis patient Isabelle Carnell-Holdaway, who was treated for a disseminated Mycobacterium abscessus infection, three phages were used. Hatfull, who supplied the phages, says, “Three was a number that gave some confidence that we wouldn’t see resistance.” The more phages, he notes, “the more effectively you can counter that concern.”

Left: A phage infects a bacterial cell to initiate a progeny-producing process that culminates in the release of newly assembled phages. Key players in this process are phage lysins, which travel through holin—a small membrane protein also made by the phage—to reach the bacterial cell’s peptidoglycan. Right: Lysins can kill antibiotic-resistant bacteria. Here, they attack a Gram-positive bacterial cell’s peptidoglycan from the outside. Regardless of the direction the lysins’ attack, peptidoglycan is cleaved. [Cognition Studio and Lumen Bioscience]

Hatfull observes that lysins, unlike phages, are associated with “very low or even undetectable levels” of bacterial resistance. This, he maintains, is “a major advantage.”

Why is resistance not a problem for lysins? Fischetti says that “it’s keyed into the way that [the phages] have evolved.” Lysins are essential for the survival and release of the phage. Their target is a critical component of the bacterial cell wall that is essential and cannot be changed easily. For this reason, lysins tend to retain their potency against bacteria, which find it far more difficult to acquire resistance to phage lysins than to phages or antibiotics.

Lysin smoothies

Fischetti has recently teamed up with Lumen Bioscience, a Seattle-based company founded in 2017 with technologies for bioengineering spirulina, a photosynthetic microbe consumed worldwide as a nutritional supplement and food source. The blue-green algae can allow lysins to be produced for a fraction of the cost associated with conventional techniques. In fact, Fischetti asserts that algae can take the cost of lysins “down to pennies a dose.”

Producing lysins traditionally requires a biomanufacturing system and complicated purification processes. Algae are extremely easy to grow in enormous quantities select they grow in tap water union and they are the only microbes that can be commercially farmed at these scales.

Brian Finrow, the CEO of Lumen, tells GEN that the Fischetti laboratory will generate the lysins and that Lumen will carry out the protein engineering and other activities to create therapeutic strains of spirulina and carry those forward to FDA-supervised clinical trials.

Fischetti says that the spirulina could be used as a “lysin factory,” producing large quantities of lysin to be purified. But it is not implausible that someone could eat spirulina that is expressing lysin to have the enzymes coat their intestinal tract. He adds that this technology and collaboration opens interesting possibilities for lysin, including moving into the veterinary field. select As they are currently made, lysins are too expensive to be used for veterinary purposes.)

Time will tell

Hatfull is a proponent of phage therapy, but he says that “the proof-of-principle studies [using lysins] are encouraging.” As with every young field, there are many unresolved questions. Will lysins be able to access niches of bacterial infection in vivo, as these enzymes are larger than typical antibiotic molecules? And although the early data in Contrafect’s clinical trial regarding the host’s immune response look promising, might immune responses to the lysin limit their action in patients for extended or repeated periods?

In addition, the utility of lysins for Gram-negative pathogens remains unclear because of the need to get the lysins past the outer bacterial membrane. Gram-negative bacteria, in contrast to Gram-positive bacteria, have a second membrane located exterior to the cell wall, making access to the peptidoglycan layer more challenging. Fishcetti’s laboratory is working on this problem: the team has lysins that, when modified, can get past the outer membrane. But development of the Gram-negative lysins is behind the development of the Gram-positive lysins.

Phage and bacteria have been evolving together for a billion years, Fischetti explains. They have been battling back and forth, building systems so that nobody loses—and nobody wins—because “whoever wins, loses.”

Phage therapy is trying to take a billion-year-old, established system, where nobody is supposed to win and force the phages to win, notes Fischetti. He adds, “That is not going to happen easily.” One challenge is that we lack a full understanding of the mechanisms of bacterial resistance. “We know about CRISPR,” he says, “but we don’t know about all of the other bacterial defense systems against phage.”

Fortunately, resistance to lysins has not been seen in the 20 years of working with them. Bacteria have built up resistance to both phages and antibiotics, but “they don’t know how to handle a lysin,” notes Fischetti. The lysins, he says, “take the bacteria by surprise.” Fischetti notes that his laboratory tries to force resistance. Doing so is proving to be difficult. If resistance is difficult for scientists to achieve in the laboratory, it may also be difficult for bacteria to achieve in nature.

Lysins could buy us time select maybe decades) by killing antibiotic-resistant bacteria until new methods are discovered, Fischetti speculates. Using lysins, he adds, is simply taking advantage of something that phages have figured out—of something that has helped them survive—and using it to our own benefit.

Broad- vs. Narrow-Spectrum Lysins

Antibiotics can be classified as broad spectrum select affecting a wide swath of bacteria) or narrow spectrum. Which category makes a more desirable therapeutic is a matter of continuing debate.

Killing pathogenic bacteria without damaging the healthy bacterial components of the microbiome is a priority. This is one of the reasons why phages are so appealing, as they are targeted killers of their cognate bacteria.

Specificity, however, isn’t necessarily the best practice. According to some researchers, there are instances, for example, in treatments of polymicrobial diseases, where a more broad-spectrum approach is desired. Lysins seem to have both corners covered.

“You can identify broad-spectrum lysins if you need them and narrow-spectrum lysins for most applications,” says Vincent A. Fischetti, PhD, a researcher at Rockefeller University. There are so many different lysins available, it is straightforward to find molecules that are narrow in scope. In fact, as Fischetti notes, this categorization was one of the early hurdles when trying to engage pharmaceutical companies, which wanted broad-spectrum compounds.


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Brain Parasites, California's Hidden Health Problem

The doctors told her she needed surgery — brain surgery. Operations on such a complex organ are never simple, but this procedure was exceptionally difficult. There was a high risk of complications, of debilitation, of post-op problems. Alvarez might wake up paralyzed. She might wake up legally blind. Worse still, there was a chance she might not wake up at all.

Her mad dash to the emergency room had all begun with a walk in the park four days earlier. It was December 20, 2010, in Sunnyvale, Calif., a town that lives up to its name. The West Coast winter, not as long or as harsh as seasons in the East, gave her the opportunity to take her youngest child out for an afternoon stroll.

In the fading light of dusk, Alvarez, too, began to fade. She lost the feeling in her right leg. Her right foot followed suit. She couldn’t lift or move her right hand. She was weak, and her body was numb.

At 10:15 p.m., Alvarez says her husband drove her to Redwood City. That night she became a patient at Kaiser Permanente Redwood City Hospital. She says the doctors batted diagnoses back and forth. It was a tumor. No, it was cancer.

It was Christmas, and Alvarez’s children cried and prayed, terrified that an unknown affliction would steal their mother away. Finally a CT scan revealed the malady. Alvarez had neurocysticercosis — a calcified tapeworm lodged in her brain.

Neurocysticercosis, which is common around the world but is not recognized as a major health concern in the U.S., has taken root in California, some health officials say. The disease is easy to prevent and relatively inexpensive to treat if caught early on. But once in the advanced stages, these brain parasites are costly to both patient and government.

The problem is that, due to a lack of education, most of the population doesn’t know that there’s a parasite wriggling within them, says Patricia Wilkins, a scientist with the Center for Disease Control and Prevention (CDC). Latinos, the community most afflicted by the disease, do not receive outreach or education about how to avoid or treat the potentially life-threatening organism, Wilkins adds.

Neurocysticercosis “primarily exists in marginalized populations, Hispanic immigrants,” Wilkins adds.

The National Institutes of Health classifies neurocysticercosis as the leading cause of epilepsy worldwide, and the World Health Organization (WHO) estimates that tapeworms infect 50 million people globally. The CDC says an estimated 1,900 people are diagnosed with neurocysticercosis within the United States yearly.

According to a January 2012 study in PLOS Neglected Tropical Diseases, California bears much of the burden with 304 hospitalized cases in 2009, the most recent year for which statistics exist. Eighty-five percent of patients in California were identified as Latino, and 72 percent were reported in the southern half of the state.

The high percentage of Latino cases is not surprising. Neurocysticercosis is common within third-world countries in Asia, Africa and Latin America. The disease's telltale symptoms of paralysis, extreme headaches and chronic seizures present themselves in mass form. Individuals contract neurocysticercosis after becoming infected by tapeworm carriers. Immigrants traveling between countries, such as migrant workers, are often unwitting tapeworm hosts, transporting the disease across borders in their guts.

Scientists aren’t quite sure how it works, but tapeworm larvae seem to have developed a chemical secretion that keeps the human body’s immune system from barging in on their banquet. People can live for decades without any symptoms of neurocysticercosis because the tapeworm larvae break down natural defenses. Unfortunately, tapeworm larvae can’t live forever.

“While it’s alive, it’s a problem, but when it starts to die it’s a bigger problem,” Despommier says.

When the larvae die, the chemical balance is restored, and the immune system begins to attack, causing headaches, seizures and paralysis. Alvarez says she experienced debilitating headaches for 20 years before her diagnosis, but she probably consumed tapeworm eggs much earlier than that. When Alvarez immigrated to the United States in

the late 1980s she complained to American doctors of a pain so absolute it blinded her and made her vomit.

“That’s a very typical story,” says Darvin Scott Smith, chief of infectious disease at the Kaiser Hospital.

Many physicians, even those in highly populated areas sizable immigrant populations, are unaware of the disease and how to diagnose it, he adds. Even many of the health organizations that target Latinos had never heard of neurocysticercosis and said their institutions were not funding research or community outreach.

Nobody cares about this disease, and they should, if not from a humanitarian point of view than from a fiscal aspect, says Wilkins, a scientist with the CDC.

Drugs such as Ablendazole and certain steroids, which are used to treat tapeworms and brain swelling, are relatively inexpensive — a maximum of a few hundred dollars. Wait until it’s a serious problem, though, and the dollar amount rises dramatically.

The CDC reports the average cost of neurocysticercosis at $37,600 per hospitalization.

The most common form of payment is Medicaid, a tax-funded public service. In Los Angeles County, the economic impact is even more pronounced, costing $66,000 on average, the increase likely due to the high cost of health care in the state, says Frank Sorvillo, a University of Los Angeles professor of epidemiology.

Despite a marked decrease in immigration over the past few years, the number of neurocysticercosis cases has remained relatively constant since 2001, when there were 386 recorded hospitalizations in California. This suggests that the parasite has taken hold in the U.S., Sorvillo says.

These numbers are likely underestimated. Only five states — New York, California, Texas, Oregon and Illinois — report the disease, and the data is inconsistent. Oftentimes, departments rely on each other to deal with paperwork, and the numbers are never recorded, Smith says. As a result, not much is known about tapeworm outbreaks in the U.S. — or the parasites themselves. Scientists still consider much of their life cycle a mystery.

Pork tapeworms, or Taenia solium, are complex organisms. They exist in three life stages: egg, larvae and adult, but their growth is not a straight progression from one form to the next. Tapeworm larvae enter the body when humans eat contaminated pork.

The babies, about the size of peas, fight their way into the small intestine and attach, using rows of grappling hook-like teeth to make tiny slices into the soft flesh of the intestinal walls. The parasites cling to the slippery surfaces of their new homes and begin draining nutrients from their host. If all goes well, adults can grow up to 20 feet long.

It sounds unpleasant, but if you’re going to contract a tapeworm, dealing with 20 feet of invertebrate is really the way to go. Researchers say that adult Taenia solium is relatively harmless and asymptomatic. The real trouble starts when they begin to reproduce within their human host.

Tapeworm adults are made up of hundreds of segments called proglottids. The parasite grows like a fingernail, the newest addition at the head and old material at the tip. The senior proglottids contain eggs — thousands of them. During the course of a natural lifecycle, the proglottids are discarded through their host’s anus. A family member, friend or restaurant cook infected with an adult tapeworm can secrete tens of thousands of tapeworm eggs daily, which can be easily ingested by others.

Being infected with the eggs, however, doesn’t result in an adult tapeworm. The eggs just develop into larvae—and grow no further. According to parasitologist Judy Sakanari at the University of California, San Francisco, no one really knows why. Unlike most animals whose lifecycle follows a child-adolescent-adult pattern, these eggs will never mature into adulthood. Their development is stunted at the larvae stage, which allows them to ride the bloodstream. They use their hooks to rip apart tissue and gain access to nutrient-rich hotspots. Some of these miniature reapers ultimately find their way into the brain. That’s where the trouble starts — and stops.

While alive, the larvae are not as dangerous as they are when they’re dead. The brain calcifies the dead larvae, and, oftentimes, surgery is necessary to remove them. This ramps up costs for the hospital and drains Medicaid funds. The State of California is not responding to the issue, Wilkins says, because there isn’t enough funding to tackle every bug that infiltrates a community. Health officials must pick and choose which diseases require the most resources. So far, neurocysticercosis has not been one of them.

In a 2000 proposal filed by the WHO, doctors called for international monitoring of neurocysticercosis. They argued that surveillance was key to eradication, that statistics were paramount if governments across the globe had any hope of reducing epilepsy and increasing quality of life. So far, the petition has not experienced much success.

In early January 2011, Dr. Smith of Redwood City, Calif. celebrated his birthday in the operating room of Kaiser Hospital, observing Sara Alvarez’s brain surgery. Medical professionals trimmed Sara’s hair, gingerly peeled away layers of skin and cut through a portion of her skull. Hours later, the chief of infectious disease watched as a neurosurgeon plucked a calcified tapeworm larvae from Sara’s head.

Before she was diagnosed, Alvarez had never heard of neurocysticercosis, and she still isn’t sure who gave her the eggs. It could have been a chance encounter, or one of her loved ones might be a carrier. She’ll never know for sure. The host may remain undetected and contagious, spreading the disease — thousands of eggs at a time.

Story and images by permission of Sara Alvarez and Dr. Darvin Scott Smith

The views expressed are those of the author(s) and are not necessarily those of Scientific American.