At CWEB, we are always looking to expand our network of strategic investors and partners. If you're interested in exploring investment opportunities or discussing potential partnerships and serious inquiries. Contact:jacque@cweb.com
Addiction to any drug — be it alcohol, tobacco, opioids or illicit drugs, like cocaine — is a chronic disease that causes a compulsive drug-seeking behavior individuals find difficult or impossible to control even when they are aware of the harmful, often deadly consequences.
Long-term use changes the structure of brain regions linked to judgment, stress, decision-making and behavior, making it increasingly difficult to ignore drug cravings.
I am a postdoctoral researcher in the laboratory of Ming Xu at the University of Chicago, where we study addiction, with a goal of finding an effective cure. In a paper in Nature Biomedical Engineering, we describe a new approach, which we developed and tested, that blocks cocaine-seeking in mice and actually protects them from high doses that would otherwise be deadly.
How can gene therapy stop addiction?
Present in human liver and blood is a natural enzyme called butyrylcholinesterase, which we abbreviate as BChE. One of this enzyme’s jobs is to break down, or metabolize, cocaine into inactive, harmless components. In fact, there is even a mutant human BChE (hBChE), which was genetically engineered to greatly accelerate the metabolism of cocaine. This super mutant enzyme is expected to become a therapy for treating cocaine addiction. However, delivering the active enzyme to addicts by injection and keeping this enzyme functioning in living animals is challenging.
So instead of giving the enzyme to the animals, we decided to engineer skin stem cells that carried the gene for the BChE enzyme. This way the skin cells would be able to manufacture the enzyme themselves and supply the animal.
In our study, we first used the gene-editing technique CRISPR to edit the mouse skin stem cells and incorporate the hBChE gene. These engineered skin cells produced consistent and high levels of the hBChE protein, which they then secreted. Then we grew these engineered stem cells in the lab and created a flat layer of skin-like tissue which took a few days to grow.
Once the lab-grown skin was complete, we transplanted it into host animals where the cells released significant quantities of hBChE into blood for more than 10 weeks.
With the genetically engineered skin graft releasing hBChE into the blood stream of the host mice, we hypothesized that if the mouse consumed cocaine, the enzyme would rapidly chop up the drug before it could trigger the addictive pleasure response in the brain.
‘Immunizing’ against cocaine
Cocaine works by elevating dopamine levels in the brain which then result in feelings of reward and euphoria, which trigger a craving for more of the drug.
The animals that received the engineered skin graft were able to clear injected quantities of cocaine faster than control animals. Their brains also had lower levels of dopamine.
Moreover, the skin grafts of hBChE-producing cells can effectively decrease the rate of lethal overdoses from 50 percent to zero when the animals were injected with a high, potentially lethal, dose of cocaine. When animals were given a lethal dose, all the control animals died while none of the animals that received the engineered skin perished. It was as if the enzyme produced by the skin graft had immunized the mice against a cocaine overdose.
We then assessed whether hBChE-producing cells can protect against development of cocaine-seeking. We used mice that were trained to reveal their preference for cocaine by spending more time in a cocaine-rich environment. Under the same dosage and training procedures, normal animals acquired preference to cocaine, whereas host animals with the skin graft showed no such preference, indicating skin graft of the hBChE-cells efficiently blocks the cocaine-induced reward effect. In a similar way, skin-derived hBChE efficiently and specifically disrupts recurrence of cocaine-seeking after 25 days of withdrawal.
To test whether this gene therapy approach will work in humans, we grew human skin-like tissue from primary skin stem cells that were genetically edited by CRISPR to allow hBChE production.
We were encouraged to see that engineered human epidermal cells produced large quantities of hBChE in cells cultured in the lab and in mice. This suggests the concept of skin gene therapy may be effective for treating cocaine abuse and overdose in humans in the future.
Adapting this approach for humans could be a promising way for blocking addiction. But first we must have sufficient evidence that it works well with few side effects. Likewise, engineering skin cells with the enzymes that degrade alcohol and nicotine could be an effective strategy for curbing addiction and abuse of these two drugs as well.
I’m not sure why a movie was made about Blaze Foley (Ben Dickey), who was, at best a minor, minor player of Texas Outlaw Music (which is like being a utility player for Ponca City in the Class D league). For some reason Ethan Hawke made this movie (producing and directing) based on Living in the Woods in a Tree: RememberingBlaze Foley, a biographical book about Blaze Foley written by Sybil Rosen (Alia Shawkat), who was Foley’s girlfriend for a while.
According to this film Foley was a drunken, drug-addled hothead who wasn’t even successful singing in dumpy bars in front of people who were less than enthusiastic about his performances. That’s about all he accomplished in life except for three studio albums that never saw the light of day and were lost, and having Willie Nelson, Merle Haggard, and Lyle Lovett each cover one of his songs.
The story is told by someone interviewing two of his friends, one of whom was Townes Van Sandt (Charlie Sexton), another drug-addicted singer, who was as big a loser as Foley (real name Michael David Fuller). Whenever Van Sandt appears on the screen, he sniffs because of his drug addiction and swallows, which probably the most annoying part of this annoying movie.
On the plus side, the acting is quite good. Dickey is a talented singer/guitarist. Sexton looks a lot like the real Van Sandt (who died in 1997). Shawket does the best she can with a role that doesn’t require much. The film never does explain why she, or anyone, would love Foley. Kris Kristofferson is advertised as a co-star, but he’s in only one scene in which he sits on the mattress of a bed and smiles. The music isn’t bad but certainly not enough to make the guy a legend or worthy of a biopic.
That males are naturally promiscuous while females are coy and choosy is a widelyheld belief. Even many scientists — including some biologists, psychologists and anthropologists — tout this notion when interviewed by the media about almost any aspect of male-female differences, includingin human beings. In fact, certain human behaviors such as rape, marital infidelity and some forms of domestic abuse have been portrayed as adaptive traits that evolved because males are promiscuous while females are sexually reluctant.
These ideas, which are pervasive in Western culture, also have served as the cornerstone for the evolutionary study of sexual selection, sex differences and sex roles among animals. Only recently have some scientists — fortified with modern data — begun to question their underlying assumptions and the resulting paradigm.
It all comes down to sperm and eggs?
These simple assumptions are based, in part, on the differences in size and presumed energy cost of producing sperm versus eggs — a contrast that we biologists call anisogamy. Charles Darwin was the first to allude to anisogamy as a possible explanation for male-female differences in sexual behavior.
His brief mention was ultimately expanded by others into the idea that because males produce millions of cheap sperm, they can mate with many different females without incurring a biological cost. Conversely, females produce relatively few “expensive,” nutrient-containing eggs; they should be highly selective and mate only with one “best male.” He, of course, would provide more than enough sperm to fertilize all a female’s eggs.
In 1948, Angus Bateman — a botanist who never again published in this area — was the first to test Darwin’s predictions about sexual selection and male-female sexual behavior. He set up a series of breeding experiments using several inbred strains of fruit flies with different mutations as markers. He placed equal numbers of males and females in laboratory flasks and allowed them to mate for several days. Then he counted their adult offspring, using inherited mutation markers to infer how many individuals each fly had mated with and how much variation there was in mating success.
One of Bateman’s most important conclusions was that male reproductive success — as measured by offspring produced — increases linearly with his number of mates. But female reproductive success peaks after she mates with only one male. Moreover, Bateman alleged this was a near-universal characteristic of all sexually reproducing species.
In 1972, theoretical biologist Robert Trivers highlighted Bateman’s work when he formulated the theory of “parental investment.” He argued that sperm are so cheap (low investment) that males evolved to abandon their mate and indiscriminately seek other females for mating. Female investment is so much greater (expensive eggs) that females guardedly mate monogamously and stay behind to take care of the young.
In other words, females evolved to choose males prudently and mate with only one superior male; males evolved to mate indiscriminately with as many females as possible. Trivers believed that this pattern is true for the great majority of sexual species.
The problem is, modern data simply don’t support most of Bateman’s and Trivers’ predictions and assumptions. But that didn’t stop “Bateman’s Principle” from influencing evolutionary thought for decades.
In reality, it makes little sense to compare the cost of one egg to one sperm. As comparative psychologist Don Dewsbury pointed out, a male produces millions of sperm to fertilize even one egg. The relevant comparison is the cost of millions of sperm versus that of one egg.
In addition, males produce semen which, in most species, contains critical bioactive compounds that presumably are very expensive to produce. As is now also well-documented, sperm production is limited and males can run out of sperm — what researchers term “sperm depletion.”
If sperm were as inexpensive and unlimited as Bateman and Trivers proposed, one would not expect sperm depletion, sperm allocation or male mate choice.
Assumptions about females don’t match reality
Birds have played a critical role in dispelling the myth that females evolved to mate with a single male. In the 1980s, approximately 90 percent of all songbird species were believed to be “monogamous” — that is, one male and one female mated exclusively with one another and raised their young together. At present, only about 7 percent are classified as monogamous.
Because of the assumption that reluctant females mate with only one male, many scientists initially assumed promiscuous males coerced reluctant females into engaging in sexual activity outside their home territory. But behavioral observations quickly determined that females play an active role in searching for nonpair males and soliciting extra-pair copulations.
Rates of EPCs and EPFs vary greatly from species to species, but the superb fairy wren is one socially monogamous bird that provides an extreme example: 95 percent of clutches contain young sired by extra-pair males and 75 percent of young have extra-pair fathers.
This situation is not limited to birds — across the animal kingdom, females frequently mate with multiple males and produce broods with multiple fathers. In fact, Tim Birkhead, a well-known behavioral ecologist, concluded in his 2000 book “Promiscuity: An Evolutionary History of Sperm Competition,” “Generations of reproductive biologists assumed females to be sexually monogamous but it is now clear that this is wrong.”
Ironically, Bateman’s own study demonstrated the idea that female reproductive success peaks after mating with only one male is not correct. When Bateman presented his data, he did so in two different graphs; only one graph (which represented fewer experiments) led to the conclusion that female reproductive success peaks after one mating. The other graph — largely ignored in subsequent treatises — showed that the number of offspring produced by a female increases with the number of males she mates with. That finding runs directly counter to the theory there is no benefit for a “promiscuous” female.
So if closer observation would have disproved this promiscuous male/sexually coy female myth, in the animal world at least, why didn’t scientists see what was in front of their eyes?
Bateman’s and Trivers’ ideas had their origins in Darwin’s writings, which were greatly influenced by the cultural beliefs of the Victorian era. Victorian social attitudes and science were closely intertwined. The common belief was that males and females were radically different. Moreover, attitudes about Victorian women influenced beliefs about nonhuman females. Males were considered to be active, combative, more variable, and more evolved and complex. Females were deemed to be passive, nurturing; less variable, with arrested development equivalent to that of a child. “True women” were expected to be pure, submissive to men, sexually restrained and uninterested in sex — and this representation was also seamlessly applied to female animals.
Although these ideas may now seem quaint, most scholars of the time embraced them as scientific truths. These stereotypes of men and women survived through the 20th century and influenced research on male-female sexual differences in animal behavior.
Unconscious biases and expectations can influence the questions scientists ask and also their interpretations of data. Behavioral biologist Marcy Lawton and colleagues describe a fascinating example. In 1992, eminent male scientists studying a species of bird wrote an excellent book on the species — but were mystified by the lack of aggression in males. They did report violent and frequent clashes among females, but dismissed their importance. These scientists expected males to be combative and females to be passive — when observations failed to meet their expectations, they were unable to envision alternative possibilities, or realize the potential significance of what they were seeing.
The same likely happened with regard to sexual behavior: Many scientists saw promiscuity in males and coyness in females because that is what they expected to see and what theory — and societal attitudes — told them they should see.
In fairness, prior to the advent of molecular paternity analysis, it was extremely difficult to accurately ascertain how many mates an individual actually had. Likewise, only in modern times has it been possible to accurately measure sperm counts, which led to the realization that sperm competition, sperm allocation and sperm depletion are important phenomena in nature. Thus, these modern techniques also contributed to overturning stereotypes of male and female sexual behavior that had been accepted for more than a century.
Besides the data summarized above, there is the question of whether Bateman’s experiments are replicable. Given that replication is an essential criterion of science, and that Bateman’s ideas became an unquestioned tenet of behavioral and evolutionary science, it is shocking that more than 50 years passed before an attempt to replicate the study was published.
Counterevidence, evolving social attitudes, recognitions of flaws in the studies that started it all — Bateman’s Principle, with its widely accepted preconception about male-female sexual behavior, is currently undergoing serious scientific debate. The scientific study of sexual behavior may be experiencing a paradigm shift. Facile explanations and assertions about male-female sexual behaviors and roles just don’t hold up.
In the two years since Russia made headlines for targeting an American political organization — the Democratic National Committee — and undermining Hillary Clinton’s race for the presidency, Russian information warfare tactics have come a long way. That includes using more subtle means of hiding their traces. Recently, Microsoft announced that it had detected Russians targeting conservative think tanks.
The Russians are not just aiming to influence political activities in the U.S. Rather, it’s extremely likely that they will soon target American civic society. They’re the local sports teams, charities, Kiwanis and Lions clubs, churches and even community groups like the Boy Scouts. Those are the groups that knit together a community and a society, providing connections that keep legitimate disagreement from exploding into acrimony and sharp divisions.
It may be hard to imagine Russia going after the Boy Scouts. But consider how Russia is seeking to sow social disconnection and mistrust in Europe. The Kremlin uses disinformation campaigns and other disruptive tools to “sow discord among European Union member states [and] destabilize European polities,” according to a 2016 Atlantic Council report. For instance, a deliberately false news story planted by the Russian government claiming that an Arab migrant had raped a Russian-German teenager exacerbated tensions over Germany’s immigration policies.
Russia is trying to create similar social tension in the U.S. — because an America that is tearing itself apart will be unable to contest Russia internationally.
A similar technique appears to have been used against Texas Democrat Beto O’Rourke’s Senate campaign, in which text messages purporting to be from inside his campaign offered to transport undocumented voters to the polls. The texts were from the campaign — but from a first-time “volunteer” who had signed up under a fake identity. O’Rourke’s campaign quickly disavowed the texts, but the bad taste they created won’t fade as fast. There’s no indication this specific incident was Russian-made, but the example illustrates the type of activity they use to create discord.
The role of social media
Social media gives Russians — and any other adversaries — a perfect tool to foment civic disruption. First, attackers can claim to be in, or from, the U.S., deceiving other users about aspects of their identities. In addition, social media has been designed to be addictive; pulling people toward more extreme views helps keep them hooked. As people are exposed to these views, and their social community shifts, they may find their views changing as well.
The mayor of a German town was stabbed in the neck in 2017 by a local resident upset at his welcoming attitude toward refugees. AP Photo/Martin Meissner
In Germany, for instance, a town whose residents used Facebook a lot started out embracing refugees: “So many locals volunteered to help” that the refugee integration center was almost overwhelmed. But then came a rise in hate crimes against the newcomers — while towns whose people used Facebook less saw smaller increases in violence.
All of those changes, raising legitimate questions about equality and humanity, involved heated discussions in the scouting community and the wider society. Now imagine that an outside group — one whose only goal was discord — jumped in to deliberately inflame the debate.
Protecting society as a whole
The Russians are coming for American society. They’ve attacked national organizations; it’s only a matter of time until they go after the less protected local groups.
People need better ways to resist the attacks. Technical protections can help. Individuals can improve their cybersecurity, opting for stronger login requirements. Internet companies can develop tools that quickly identify fake accounts and better vet clients to prevent promotions of phony content. But technology can only do so much. Defense is social, not technical.
The Nordic countries — Denmark, Finland, Norway, Sweden — have had great success combating the Russian efforts. Their defenses include knowing their enemy better, education systems that emphasize critical thinking and new efforts to teach ways to differentiate between reliable and unreliable sources and actively counter the Russian efforts.
The U.S. is starting from a different, more divided, place, and its solutions must compensate for the inherent differences of the country’s big melting pot. Given the Russian efforts at disinformation and sowing mistrust, it’s time for Americans to change their behavior.
I suggest taking sharp political disagreements offline. That may sound like a step back to the 1990s, but there’s little choice. Social media is great for sharing photos of friends and family. But for anything controversial, including political discussions and civic issues, the technology creates an unequal playing field, making extremism and outrage easier than reason and calm. With adversaries attacking in force, Americans should be responding strongly to protect themselves. What’s at stake is the very society we share.
Some movies are terrible from the get go. Others grab you right away and keep you riveted. This is the latter. Based on the true story of Richard Wershe Sr. (Matthew McConaughey) and his teenage son, Rick Jr. (Richie Merritt in his acting debut), Rick becomes a police informant and a drug dealer beginning when he is only 15 years old.
Directed by Yann Demange from a script by Andy Weiss and Logan & Noah Miller, the dialogue, direct from the streets, is authentic and credible. Merritt and McConaughey give Oscar ®-quality performances and they are ably backed up by Jennifer Jason Leigh and Rory Cochrane as the FBI agents who begin working with Rick as a confidential informant, and Brian Tyree Henry as narcotics Detective Jackson; Bruce Dern as Rick’s grandfather, Roman “Ray” Wershe; Piper Laurie, who went to my Junior High School (long before me), as Rick’s grandmother, Verna Wershe; and last but not least Bel Powley as Rick’s sister, Dawn. In fact, if there is a performance that is exceeded only by Merritt’s, it is Powley’s.
Rick was the youngest FBI informant ever. The story is told through a tempestuous, byzantine relationship between Rick and his father, who is a consummate hustler trying to bring up a son and a daughter and provide for them doing things like buying guns and reselling them, a pretty sleazy guy on the outskirts of respectability. But he clearly loves his children, and most of what he does seems to be to help them, however misguided his advice might be.
Rick feels responsibility for his sister, who is involved with a bad boyfriend and drugs, and his father, so he feels compelled to do things he knows aren’t right.
Rick and his father come face to face with the terrible corruption of Detroit police, politicians, and the FBI, and are clearly overmatched. This is a heart-wrenching but captivating film whose tension never lags.
Although filmed in Cleveland, cinematographer Tat Radcliffe and Production Designer Stefania Cella brilliantly reproduced the stagnating atmosphere of Detroit in the 1980s. This unique ambience is an essential character in the movie.
Despite the presence of Oscar ®-winning McConaughey, the star of the movie is Merritt. He is in almost every scene and he carries the film with a truly remarkable performance, especially considering it’s his debut.
Spoiler Alert: This film clearly has a POV, however I am not convinced. It is undisputed that after he was an informant he became a big time drug dealer. The movie, which takes the position that he was railroaded and left out to dry by his law enforcement handlers, pretty much glosses over that fact.
Normally I loathe movies like this. One person taking on hundreds of people and emerging relatively unscathed. But this revenge movie is as well done as it could be, I guess, given what it is. I’d like a shot at a movie like this. I’d make the confrontations more or less believable. Not so many villains succumbing to one heroine. Believable fights, not blows so bad one can kill, but certainly disable for the foreseeable future; wounds with consequence.
But, forget that. This is a genre and genres apparently have rules. And one rule for this genre is; make it absurd.
Directed by Pierre Morel from a script by Chad St. John, Jennifer Garner is the super heroine who can’t be defeated by mere mortals. Her son and daughter are killed by members of a drug gang. She survives and devotes the rest of her life to revenge, taking on the biggest and the baddest, always outnumbered, like 20 to 1.
That’s about it. It’s a feel good movie because lots of bad guys who deserve to die, do. ‘Nuff said.
This is a terrific tale of a female High Court Judge in England, Fiona Maye (Emma Thompson), who is faced with a life-changing decision on seventeen-year-old Adam (Fionn Whitehead), who has Leukemia but is refusing a blood transfusion because it violates his Jehovah’s Witness faith. At the same time, she is having to deal with a terrible problem in her marriage.
What is wonderful about the movie is it shows how much certitude she has in her courtroom decisions but how difficult it is for her to face up to the personal problems in her marriage.
Beautifully directed with fine pace by Richard Eyre from a script by Ian McEwan, who wrote the 2014 novel, Thompson grabs the role and owns it. On the one hand she is a confident, powerful woman who, in her position as a Judge, epitomizes what Irving Thalberg, the legendary head of Production and MGM, said when asked if he ever had doubts. He answered,
Supposing there’s got to be a road through the mountain and… there seems to be a half-dozen possible roads… each one of which, so far as you can determine, is as good as the other. Now suppose you happen to be the top man, there’s a point where you don’t exercise the faculty of judgment of the ordinary way, but simply the faculty of arbitrary decision. You say, “Well, I think we will put the road there,” and you trace it with your finger and you know in your secret heart, and no one else knows, that you have no reason for putting the road there rather than in several other different courses, but you’re the only person who knows that you don’t know why you’re doing it and you’ve got to stick to that and you’ve got to pretend that you know that you did it for specific reasons, even though you’re utterly assailed by doubts at times as to the wisdom of your decision, because all these other possible decisions keep echoing in your ear. But when you’re planning a new enterprise on a grade scale, the people under you mustn’t ever know or guess that you’re in doubt, because they’ve all got to have something to look up to and they mustn’t ever dream that you’re in doubt about any decision.
That’s the way Fiona is in her courtroom when faced with important decisions often affecting life and death. But when faced with her own dilemma, she lacks such certitude and runs away from facing up to the problem. It’s a brilliant dichotomy and McEwan treats it with sensitivity and perception.
Equally effective is Stanley Tucci as Fiona’s husband, Jack. Starved of affection, he candidly tells Fiona that he is going to embark on an affair because their marriage is not supplying him with everything he needs. While threatening infidelity is generally not too admirable, the way Jack approaches Fiona it seems an imminently logical solution to the problem. That’s not the way Fiona sees it, though.
Bolstered by outstanding performances by Thompson, Whitehead, and Tucci, Fiona wrestles through these problems throughout, and the movie never lags, even for a second.
This makes it all the more imperative to get early and accurate forecasts out to the public, something researchers like us are actively contributing to.
Making predictions
Hurricane forecasts have traditionally focused on predicting a storm’s track and intensity. The track and size of the storm determine which areas may be hit. To do so, forecasters use models — essentially software programs, often run on large computers.
Unfortunately, no single forecast model is consistently better than other models at making these predictions. Sometimes these forecasts show dramatically different paths, diverging by hundreds of miles. Other times, the models are in close agreement. In some cases, even when models are in close agreement, the small differences in track have very large differences in storm surge, winds and other factors that impact damage and evacuations.
What’s more, several empirical factors in the forecast models are either determined under laboratory conditions or in isolated field experiments. That means that they may not necessarily fully represent the current weather event.
So, forecasters use a collection of models to determine a likely range of tracks and intensities. Such models include the NOAA’s Global Forecast System and European Centre for Medium-Range Weather Forecasts global models.
The FSU Superensemble was developed by a group at our university, led by meteorologist T.N. Krishnamurti, in the early 2000s. The Superensemble combines output from a collection of models, giving more weight to the models that showed better predicted past weather events, such as Atlantic tropical cyclone events.
A forecaster’s collection of models can be made larger by tweaking the models and slightly changing the starting conditions. These perturbations attempt to account for uncertainty. Meteorologists cannot know the exact state of the atmosphere and the ocean at the time of the start of the model. For example, tropical cyclones are not observed well enough to have sufficient detail about winds and rain. For another example, the sea surface temperature is cooled by the passage of a storm, and if the area remains cloud-covered these cooler waters are much less likely to be observed by satellite.
Limited improvement
Over the past decade, track forecasts have steadily improved. A plethora of observations — from satellites, buoys and aircraft flown into the developing storm — allow scientists to better understand the environment around a storm, and in turn improve their models. Some models have improved by as much as 40 percent for some storms.
That’s partly because of the metric chosen to describe the intensity of a tropical cyclone. Intensity is often described in terms of peak wind speed at a height of 10 meters above the surface. To measure it, operational forecasters at the National Hurricane Center in Miami look at the maximum, one-minute average wind speed observed at any given point in the tropical cyclone.
However, it’s extremely difficult for a model to estimate the maximum wind speed of a tropical cyclone at any given future time. Models are inexact in their descriptions of the entire state of the atmosphere and ocean at the start time of the model. Small-scale features of tropical cyclones — like sharp gradients in rainfall, surface winds and wave heights within and outside of the tropical cyclones — are not as reliably captured in the forecast models.
Both atmospheric and ocean characteristics can influence storm intensity. Scientists now think that better information about the ocean could offer the the greatest gains in forecast accuracy. Of specific interest is the energy stored in the upper ocean and how this varies with ocean features such as eddies. Current observations are not sufficiently effective at placing ocean eddies in the correct location, nor are they effective in capturing the size of these eddies. For conditions where the atmosphere doesn’t severely limit hurricane growth, this oceanic information should be very valuable.
People with severe burns, bedsores or chronic diseases such as diabetes are at risk for developing wounds known as cutaneous ulcers, which can extend through multiple layers of the skin.
Apart from being extremely painful, these wounds can lead to serious, sometimes deadly, infections or amputations. Typically, these ulcers are treated by surgically transplanting existing skin to cover the wound. However, when the ulcer is especially large, it can be challenging to graft enough skin. In such cases, researchers may isolate skin stem cells from a patient, grow them in the laboratory and transplant them back into the patient. But the procedure is time-consuming, risky for the patient and not necessarily effective.
A diabetic foot with a cutaneous ulcer. Such ulcers destroy multiple layers of skin, leading to infections. If untreated, the tissue damage may require that the toes or entire foot be amputated. Alila Medical Media/Shutterstock.com
The dramatically rising rates of diabetes alone underscore an urgent need to develop new, effective methods for the treatment of cutaneous ulcers.
My laboratory at the Salk Institute focuses on developing stem-cell-based approaches to “reprogram” cells from one type into another for the purpose of regenerative medicine.
In a report in the journal Nature, we describe a new technique to directly convert the cells naturally present in an open wound into new skin cells by reprogramming the wounded cells to a stem-cell-like state, in which cells revert to an earlier, more flexible state from which they can develop into different cell types.
A postdoctoral research associate in my lab, Masakazu Kurita, who has a background in plastic surgery, knew that a critical step in wound healing was the migration of stem-cell-like cells called basal keratinocytes — from nearby, undamaged skin — into wounds.
Basal keratinocytes are precursors to many different types of skin cells. But large, severe wounds such as cutaneous ulcers no longer have any basal keratinocytes. Moreover, as these wounds heal, the cells multiplying in the area — known as mesenchymal cells — are involved primarily in closing the wound and inflammation, but they cannot rebuild healthy skin.
We wanted to convert these mesenchymal cells into basal keratinocytes, without ever taking them out of the body.
To do so, we compared the levels of different proteins inside the two cell types — mesenchymal cells and keratinocytes — to figure out what distinguished them and find out what we would need to change in order to reprogram one cell type into the other.
We identified 55 proteins, which we call “reprogramming factors,” that are potentially involved in determining and maintaining the cellular identity of basal keratinocytes. We conducted further experiments on each potential reprogramming factor and narrowed the list down to four factors that would transform mesenchymal cells into basal keratinocytes in vitro in petri dishes. These keratinocytes then formed all the cells present in healthy new skin.
This image is a cross-section of regenerated skin with different cell types indicated with fluorescent tags. Green is keratinocytes, red is mesenchymal cells, blue is the cell nucleus and magenta marks the innermost layer of skin epithelium. Juan Carlos Izpisua Belmonte, CC BY-SA
We then tested the power of these four factors to treat skin ulcers on mice. Just 18 days after we applied a topical solution containing these four factors directly onto the ulcers, we saw healing happen. These four factors reprogrammed the mesenchymal cells in the wound into keratinocytes which then grew into the many cells types that make up healthy skin, closing and healing the sore. These cells continued to grow and join the surrounding skin, even in large ulcers. When we examined the mice three months and six months later, we saw that the newly generated cells functioned like healthy skin. Rodent skin heals differently from human skin, so there was no visible scar tissue, though it should have been there.
Further work is necessary to ensure the safety of this approach, especially over a much longer term, but as an initial test of the concept, the results are very promising.
We are optimistic that our approach represents an initial proof of principle for in vivo regeneration of an entire three-dimensional tissue, like the skin, not just individual cell types. In addition to wound healing, our approach could be useful for repairing skin damage, countering the effects of aging and helping us to better understand skin cancer.
The friendship of Michelle Obama and George W. Bush strikes a hopeful, important chord – CWEB.com
Michelle Obama hugs George W. Bush at the opening of the Smithsonian Museum of African American History and Culture on Sept. 24, 2016. Pablo Martinez Monsivais/AP
Earlier this month, a video showing George Bush passing candy to Michelle Obama at the funeral of John McCain went viral. That such a simple act of kindness should attract such wide attention is a notable sign of our divided and rancorous times. It reminds us how rare it has become to see people on a national stage treat one another kindly, as if friendship between them were a real possibility. As a physician, I can say that this apparent decline in prospects for friendship presents a real threat to our well-being.
Friendship is more important than many of us know. Aristotle, the person MIT claims exerted more influence in history than any other, declared that it is impossible to live a full human life without friends. Not surprisingly, he devoted a large portion of his most widely read work, “The Nicomachean Ethics,” to the topic. What makes friendship so important to us? What factors enable friendships to thrive? And where can we look for examples of friendship at its best?
Friendship’s benefits
One clear benefit of friendship is good health. A review of 148 studies involving over 300,000 participants found that those with robust social relationships were 50 percent more likely to survive than those with poor ones, a benefit roughly equal to quitting smoking and twice that of regular exercise. Another review found that separation and lack of social contact are strongly associated with a poor sense of well-being.
Such results should not surprise us. Aristotle wrote that human beings are social creatures. Every human infant comes into the world helpless, and it is only by virtue of years of care and child-rearing that any of us reaches maturity. The medical community is just now beginning to understand more clearly the vital role of friendship throughout the human lifespan, not just in the early years but also throughout life.
While it is possible to identify some generic features of thriving friendships, one of the best ways to understand the full richness and complexity of such relationships is to study the stories of great friends. Western literature brims with examples — Homer’s Achilles and Patroclus, the Bible’s Jonathan and David, and Jane Austen’s Charlotte and Elizabeth. But recent American history has furnished its own shining examples.
Dorothy and Peter
Consider one of the most remarkable American friendships of the 20th century, Dorothy Day (1897-1980) and Peter Maurin (1877-1949). Together they would found a movement known as the Catholic Worker, which still operates 220 houses of hospitality across the U.S.
As a young woman, Dorothy Day led a bohemian life, experiencing numerous love affairs, a failed marriage, suicide attempts and an abortion. With the birth of her daughter in 1926, she turned from her atheist common law husband to answer a religious calling. A gifted writer, she recounted her remarkable story in her 1952 autobiography, “The Long Loneliness.”
Peter Maurin was born to a poor working family in France and immigrated to America, where he worked as a French tutor. In the 1920s, inspired in part by the life of St. Francis of Assisi, he underwent a religious conversion, after which he embraced poverty as a gift from God and worked at menial jobs for room and board. Peter liked to contrast the contemporary view of beggars as bums with the ancient Greek view that they are the ambassadors of the gods.
Dorothy and Peter met in 1932. She was a journalist who had just returned from covering a hunger march in Washington, D.C., hungering herself for some cause to which she could devote her life. He was a street-corner prophet with big ideas who had failed to gain traction. She saw in him the answer to her prayers for a purpose in life, and he saw her as a person whose words and works could attract thousands to the cause.
In 1933, their new friendship really began bearing fruit. Peter suggested she start a newspaper, the Catholic Worker, which published its first issue on May 1, selling for a penny a copy. His ideas also served as the inspiration for houses of hospitality for the poor. By living with and serving the poor, Dorothy, Peter and those they attracted to the movement would not only talk and write about their ideas but also live them every day.
Dorothy and Peter could hardly have been more different. He was short, an immigrant, shabbily dressed, his pockets bulging with newspapers and pamphlets, his mind on fire with ideas. She was tall and striking, a cigarette often dangling from her mouth, and could readily inspire others to action.
Features of great friendship
Their friendship flourished first because they shared a common purpose. Such purposes might include building a thriving family, creating a business partnership, or simply bringing out the best in each other. Dorothy and Peter believed that they had been put on earth “to give people the vision of a society in which it is easier for people to be good.” Great friendship means more than enjoying one another’s company. It means sharing a vision and working to achieve it.
Second, instead of dividing them, their differences brought them more closely together. They complemented one another — Peter the absent-minded dreamer who lived in ideas, and Dorothy the activist whose street battles would land her in prison multiple times. Peter delighted in the title of agitator, but it was primarily Dorothy who would build the movement’s momentum. Each was a formidable force, but together they produced results far beyond the mere sum of their parts.
Third, their relationship depended on something far deeper than romance. Each was keenly aware of the differences between men and women, and they occasionally teased each other about them. For example, when Dorothy rejected Peter’s original name for the newspaper, he responded, “Man proposes and woman disposes.” But because they shared a deep commitment to a common purpose, each tended to find in the quirks of the other cause not for consternation but delight.
Fourth, they regarded their relationship not as a secret to be jealously guarded for their own private enjoyment, but a renewable resource that could only grow through the sharing. Wrote Dorothy, “Heaven is a banquet and life is a banquet, too, even with a crust, where there is companionship.” At first several, then dozens, and eventually hundreds of young people joined the movement. As it unfolded, they found their shared mission not diluted but intensified.
Finally, they both loved books and conversation. Peter read the Bible and the Lives of the Saints, to which Dorothy added the novels of Dickens and Tolstoy. She would frequently get to know visitors by asking them to name their favorite of Dostoevsky’s novels. They regularly discussed such books and ideas at roundtable discussions, which helped to clarify their thinking and inspire their mission. To them, reading and conversation were not pastimes. They were means of discerning and affirming life’s purpose.
Building friendships
Our fascination with a simple act of human kindness between political rivals reveals our longing to see and experience friendship. But friendship, like love, is not a dish that can be reliably prepared merely by following a recipe. To find genuine friendship and reap the many benefits it can sow, we need to explore the elements of great friendship, including a common sense of purpose, a commitment to complementarity, a delight in difference, a summons to share and a love of learning.
Perhaps the greatest wonder of friendship comes through community. Dorothy Day said, “We have all known the long loneliness, and we have learned that the only solution is love and that love comes with community.” As MIT’s second-most influential human being, Plato, wrote in his dialogue “Symposium,” in isolation we are incomplete. It is only in the union of friendships that we stand a chance of leading truly complete lives.
