Blood Money: Paying for Convalescent Plasma to Treat COVID-19
Convalescent plasma – first used to treat diphtheria in 1890 – has been dusted off the shelf to treat COVID-19. Does it work? Should we rely strictly on the altruism of donors or should people be paid for it?
The biologic theory is that a person who has recovered from a disease has chemicals in their blood, most likely antibodies, that contributed to their recovery, and transferring those to a person who is sick might aid their recovery. Whole blood won't work because there are too few antibodies in a single unit of blood and the body can hold only so much of it.
Plasma comprises about 55 percent of whole blood and is what's left once you take out the red blood cells that carry oxygen and the white blood cells of the immune system. Most of it is water but the rest is a complex mix of fats, salts, signaling molecules and proteins produced by the immune system, including antibodies.
A process called apheresis circulates the donors' blood through a machine that separates out the desired parts of blood and returns the rest to the donor. It takes several times the length of a regular whole blood donation to cycle through enough blood for the process. The end product is a yellowish concentration called convalescent plasma.
Recent History
It was used extensively during the great influenza epidemic off 1918 but fell out of favor with the development of antibiotics. Still, whenever a new disease emerges – SARS, MERS, Ebola, even antibiotic-resistant bacteria – doctors turn to convalescent plasma, often as a stopgap until more effective antibiotic and antiviral drugs are developed. The process is certainly safe when standard procedures for handling blood products are followed, and historically it does seem to be beneficial in at least some patients if administered early enough in the disease.
With few good treatment options for COVID-19, doctors have given convalescent plasma to more than a hundred thousand Americans and tens of thousand of people elsewhere, to mixed results. Placebo-controlled trials could give a clearer picture of plasma's value but it is difficult to enroll patients facing possible death when the flip of a coin will determine who will receive a saline solution or plasma.
And the plasma itself isn't some uniform pill stamped out in a factory, it's a natural product that is shaped by the immune history of the donor's body and its encounter not just with SARS-CoV-2 but a lifetime of exposure to different pathogens.
Researchers believe antibodies in plasma are a key factor in directly fighting the virus. But the variety and quantity of antibodies vary from donor to donor, and even over time from the same donor because once the immune system has cleared the virus from the body, it stops putting out antibodies to fight the virus. Often the quality and quantity of antibodies being given to a patient are not measured, making it somewhat hit or miss, which is why several companies have recently developed monoclonal antibodies, a single type of antibody found in blood that is effective against SARS-CoV-2 and that is multiplied in the lab for use as therapy.
Plasma may also contain other unknown factors that contribute to fighting disease, say perhaps signaling molecules that affect gene expression, which might affect the movement of immune cells, their production of antiviral molecules, or the regulation of inflammation. The complexity and lack of standardization makes it difficult to evaluate what might be working or not with a convalescent plasma treatment. Thus researchers are left with few clues about how to make it more effective.
Industrializing Plasma
Many Americans living along the border with Mexico regularly head south to purchase prescription drugs at a significant discount. Less known is the medical traffic the other way, Mexicans who regularly head north to be paid for plasma donations, which are prohibited in their country; the U.S. allows payment for plasma donations but not whole blood. A typical payment is about $35 for a donation but the sudden demand for convalescent plasma from people who have recovered from COVID-19 commands a premium price, sometimes as high as $200. These donors are part of a fast-growing plasma industry that surpassed $25 billion in 2018. The U.S. supplies about three-quarters of the world's needs for plasma.
Payment for whole blood donation in the U.S. is prohibited, and while payment for plasma is allowed, there is a stigma attached to payment and much plasma is donated for free.
The pharmaceutical industry has shied away from natural products they cannot patent but they have identified simpler components from plasma, such as clotting factors and immunoglobulins, that have been turned into useful drugs from this raw material of plasma. While some companies have retooled to provide convalescent plasma to treat COVID-19, often paying those donors who have recovered a premium of several times the normal rate, most convalescent plasma has come as donations through traditional blood centers.
In April the Mayo Clinic, in cooperation with the FDA, created an expanded access program for convalescent plasma to treat COVID-19. It was meant to reduce the paperwork associated with gaining access to a treatment not yet approved by the FDA for that disease. Initially it was supposed to be for 5000 units but it quickly grew to more than twenty times that size. Michael Joyner, the head of the program, discussed that experience in an extended interview in September.
The Centers for Medicare and Medicaid Services (CMS) also created associated reimbursement codes, which became permanent in August.
Mayo published an analysis of the first 35,000 patients as a preprint in August. It concluded, "The relationships between mortality and both time to plasma transfusion, and antibody levels provide a signature that is consistent with efficacy for the use of convalescent plasma in the treatment of hospitalized COVID-19 patients."
It seemed to work best when given early in infection and in larger doses; a similar pattern has been seen in studies of monoclonal antibodies. A revised version will soon be published in a major medical journal. Some criticized the findings as not being from a randomized clinical trial.
Convalescent plasma is not the only intervention that seems to work better when used earlier in the course of disease. Recently the pharmaceutical company Eli Lilly stopped a clinical trial of a monoclonal antibody in hospitalized COVID-19 patients when it became apparent it wasn't helping. It is continuing trials for patients who are less sick and begin treatment earlier, as well as in persons who have been exposed to the virus but not yet diagnosed as infected, to see if it might prevent infection. In November the FDA eased access to this drug outside of clinical trials, though it is not yet approved for sale.
Show Me the Money
The antibodies that seem to give plasma its curative powers are fragile proteins that the body produces to fight the virus. Production shuts down once the virus is cleared and the remaining antibodies survive only for a few weeks before the levels fade. [Vaccines are used to train immune cells to produce antibodies and other defenses to respond to exposure to future pathogens.] So they can be usefully harvested from a recovered patient for only a few short weeks or months before they decline precipitously. The question becomes, how does one mobilize this resource in that short window of opportunity?
The program run by the Mayo Clinic explains the process and criteria for donating convalescent plasma for COVID-19, as well as links to local blood centers equipped to handle those free donations. Commercial plasma centers also are advertising and paying for donations.
A majority of countries prohibit paying donors for blood or blood products, including India. But an investigation by India Today touted a black market of people willing to donate convalescent plasma for the equivalent of several hundred dollars. Officials vowed to prosecute, saying donations should be selfless.
But that enforcement threat seemed to be undercut when the health minister of the state of Assam declared "plasma donors will get preference in several government schemes including the government job interview." It appeared to be a form of compensation that far surpassed simple cash.
The small city of Rexburg, Idaho, with a population a bit over 50,000, overwhelmingly Mormon and home to a campus of Brigham Young University, at one point had one of the highest per capita rates of COVID-19 in the current wave of infection. Rumors circulated that some students were intentionally trying to become infected so they could later sell their plasma for top dollar, potentially as much as $200 a visit.
Troubled university officials investigated the allegations but could come up with nothing definitive; how does one prove intentionality with such an omnipresent yet elusive virus? They chalked it up to idle chatter, perhaps an urban legend, which might be associated with alcohol use on some other campus.
Doctors, hospitals, and drug companies are all rightly praised for their altruism in the fight against COVID-19, but they also get paid. Payment for whole blood donation in the U.S. is prohibited, and while payment for plasma is allowed, there is a stigma attached to payment and much plasma is donated for free. "Why do we expect the donors [of convalescent plasma] to be the only uncompensated people in the process? It really makes no sense," argues Mark Yarborough, an ethicist at the UC Davis School of Medicine in Sacramento.
"When I was in grad school, two of my closest friends, at least once a week they went and gave plasma. That was their weekend spending money," Yarborough recalls. He says upper and middle-income people may have the luxury of donating blood products but prohibiting people from selling their plasma is a bit paternalistic and doesn't do anything to improve the economic status of poor people.
"Asking people to dedicate two hours a week for an entire year in exchange for cookies and milk is demonstrably asking too much," says Peter Jaworski, an ethicist who teaches at Georgetown University.
He notes that companies that pay plasma donors have much lower total costs than do operations that rely solely on uncompensated donations. The companies have to spend less to recruit and retain donors because they increase payments to encourage regular repeat donations. They are able to more rationally schedule visits to maximize use of expensive apheresis equipment and medical personnel used for the collection.
It seems that COVID-19 has been with us forever, but in reality it is less than a year. We have learned much over that short time, can now better manage the disease, and have lower mortality rates to prove it. Just how much convalescent plasma may have contributed to that remains an open question. Access to vaccines is months away for many people, and even then some people will continue to get sick. Given the lack of proven treatments, it makes sense to keep plasma as part of the mix, and not close the door to any legitimate means to obtain it.
Fast for Longevity, with Less Hunger, with Dr. Valter Longo
You’ve probably heard about intermittent fasting, where you don’t eat for about 16 hours each day and limit the window where you’re taking in food to the remaining eight hours.
But there’s another type of fasting, called a fasting-mimicking diet, with studies pointing to important benefits. For today’s podcast episode, I chatted with Dr. Valter Longo, a biogerontologist at the University of Southern California, about all kinds of fasting, and particularly the fasting-mimicking diet, which minimizes hunger as much as possible. Going without food for a period of time is an example of good stress: challenges that work at the cellular level to boost health and longevity.
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If you’ve ever spent more than a few minutes looking into fasting, you’ve almost certainly come upon Dr. Longo's name. He is the author of the bestselling book, The Longevity Diet, and the best known researcher of fasting-mimicking diets.
With intermittent fasting, your body might begin to switch up its fuel type. It's usually running on carbs you get from food, which gets turned into glucose, but without food, your liver starts making something called ketones, which are molecules that may benefit the body in a number of ways.
With the fasting-mimicking diet, you go for several days eating only types of food that, in a way, keep themselves secret from your body. So at the level of your cells, the body still thinks that it’s fasting. This is the best of both worlds – you’re not completely starving because you do take in some food, and you’re getting the boosts to health that come with letting a fast run longer than intermittent fasting. In this episode, Dr. Longo talks about the growing number of studies showing why this could be very advantageous for health, as long as you undertake the diet no more than a few times per year.
Dr. Longo is the director of the Longevity Institute at USC’s Leonard Davis School of Gerontology, and the director of the Longevity and Cancer program at the IFOM Institute of Molecular Oncology in Milan. In addition, he's the founder and president of the Create Cures Foundation in L.A., which focuses on nutrition for the prevention and treatment of major chronic illnesses. In 2016, he received the Glenn Award for Research on Aging for the discovery of genes and dietary interventions that regulate aging and prevent diseases. Dr. Longo received his PhD in biochemistry from UCLA and completed his postdoc in the neurobiology of aging and Alzheimer’s at USC.
Show links:
Create Cures Foundation, founded by Dr. Longo: www.createcures.org
Dr. Longo's Facebook: https://www.facebook.com/profvalterlongo/
Dr. Longo's Instagram: https://www.instagram.com/prof_valterlongo/
Dr. Longo's book: The Longevity Diet
The USC Longevity Institute: https://gero.usc.edu/longevity-institute/
Dr. Longo's research on nutrition, longevity and disease: https://pubmed.ncbi.nlm.nih.gov/35487190/
Dr. Longo's research on fasting mimicking diet and cancer: https://pubmed.ncbi.nlm.nih.gov/34707136/
Full list of Dr. Longo's studies: https://pubmed.ncbi.nlm.nih.gov/?term=Longo%2C+Valter%5BAuthor%5D&sort=date
Research on MCT oil and Alzheimer's: https://alz-journals.onlinelibrary.wiley.com/doi/f...
Keto Mojo device for measuring ketones
Silkworms with spider DNA spin silk stronger than Kevlar
Story by Freethink
The study and copying of nature’s models, systems, or elements to address complex human challenges is known as “biomimetics.” Five hundred years ago, an elderly Italian polymath spent months looking at the soaring flight of birds. The result was Leonardo da Vinci’s biomimetic Codex on the Flight of Birds, one of the foundational texts in the science of aerodynamics. It’s the science that elevated the Wright Brothers and has yet to peak.
Today, biomimetics is everywhere. Shark-inspired swimming trunks, gecko-inspired adhesives, and lotus-inspired water-repellents are all taken from observing the natural world. After millions of years of evolution, nature has quite a few tricks up its sleeve. They are tricks we can learn from. And now, thanks to some spider DNA and clever genetic engineering, we have another one to add to the list.
The elusive spider silk
We’ve known for a long time that spider silk is remarkable, in ways that synthetic fibers can’t emulate. Nylon is incredibly strong (it can support a lot of force), and Kevlar is incredibly tough (it can absorb a lot of force). But neither is both strong and tough. In all artificial polymeric fibers, strength and toughness are mutually exclusive, and so we pick the material best for the job and make do.
Spider silk, a natural polymeric fiber, breaks this rule. It is somehow both strong and tough. No surprise, then, that spider silk is a source of much study.The problem, though, is that spiders are incredibly hard to cultivate — let alone farm. If you put them together, they will attack and kill each other until only one or a few survive. If you put 100 spiders in an enclosed space, they will go about an aggressive, arachnocidal Hunger Games. You need to give each its own space and boundaries, and a spider hotel is hard and costly. Silkworms, on the other hand, are peaceful and productive. They’ll hang around all day to make the silk that has been used in textiles for centuries. But silkworm silk is fragile. It has very limited use.
The elusive – and lucrative – trick, then, would be to genetically engineer a silkworm to produce spider-quality silk. So far, efforts have been fruitless. That is, until now.
We can have silkworms creating silk six times as tough as Kevlar and ten times as strong as nylon.
Spider-silkworms
Junpeng Mi and his colleagues working at Donghua University, China, used CRISPR gene-editing technology to recode the silk-creating properties of a silkworm. First, they took genes from Araneus ventricosus, an East Asian orb-weaving spider known for its strong silk. Then they placed these complex genes – genes that involve more than 100 amino acids – into silkworm egg cells. (This description fails to capture how time-consuming, technical, and laborious this was; it’s a procedure that requires hundreds of thousands of microinjections.)
This had all been done before, and this had failed before. Where Mi and his team succeeded was using a concept called “localization.” Localization involves narrowing in on a very specific location in a genome. For this experiment, the team from Donghua University developed a “minimal basic structure model” of silkworm silk, which guided the genetic modifications. They wanted to make sure they had the exactly right transgenic spider silk proteins. Mi said that combining localization with this basic structure model “represents a significant departure from previous research.” And, judging only from the results, he might be right. Their “fibers exhibited impressive tensile strength (1,299 MPa) and toughness (319 MJ/m3), surpassing Kevlar’s toughness 6-fold.”
A world of super-materials
Mi’s research represents the bursting of a barrier. It opens up hugely important avenues for future biomimetic materials. As Mi puts it, “This groundbreaking achievement effectively resolves the scientific, technical, and engineering challenges that have hindered the commercialization of spider silk, positioning it as a viable alternative to commercially synthesized fibers like nylon and contributing to the advancement of ecological civilization.”
Around 60 percent of our clothing is made from synthetic fibers like nylon, polyester, and acrylic. These plastics are useful, but often bad for the environment. They shed into our waterways and sometimes damage wildlife. The production of these fibers is a source of greenhouse gas emissions. Now, we have a “sustainable, eco-friendly high-strength and ultra-tough alternative.” We can have silkworms creating silk six times as tough as Kevlar and ten times as strong as nylon.
We shouldn’t get carried away. This isn’t going to transform the textiles industry overnight. Gene-edited silkworms are still only going to produce a comparatively small amount of silk – even if farmed in the millions. But, as Mi himself concedes, this is only the beginning. If Mi’s localization and structure-model techniques are as remarkable as they seem, then this opens up the door to a great many supermaterials.
Nature continues to inspire. We had the bird, the gecko, and the shark. Now we have the spider-silkworm. What new secrets will we unravel in the future? And in what exciting ways will it change the world?