Universal T-Cell Therapy

Universal T-cell therapies

If you have been reading our articles for a while, or generally keep up with cancer therapeutics in the news you must have heard of T-cell therapy. A big problem with current T-cell therapies is that they target a very specific marker of cancerous cells and so, when a mutation results in the cancer cells no longer expressing that marker, the cancer will relapse and evade the therapy. To address this problem, a group at the University of Pittsburgh developed a new approach wherein they had an antibody that can target a specific marker bound to a molecule called ‘BG’, which can be found by CAR-T or SynNotch-T cells, mediate the expression of a protein called ‘SNAPtag’ to kill the cancer. 

That suddenly became a lot of jargon so let’s break some of it down. First, CAR-T cells are cells expressing the chimeric antigen receptor (CAR), an artificially modified receptor that gives T-cell the ability to kill other cells expressing the target protein. SynNotch-T cells work in a similar way but work by inducing or restricting the expression of a gene. So if a SynNotch T-cell finds its target, it will induce the expression of another protein, say CAR to kill the target cell. The SNAPtag approach adds more flexibility to these therapies. With current approaches, if cancers stop expressing the protein that the therapy targets, a new therapy with a different target has to be used. This requires the designing of a new cell to put into a patients body which requires more time, more money, and introduces new unknown factors. In the case of the SNAPtag approach, if the cancer stops expressing the initial target, a new antibody against a new target can be created and linked to BG which can be put in the patients allowing the SNAPtag T-cells to target the cancer again. 

This will allow using the same set of modified T-cells to target multiple targets and treat cancer as it mutates. This may also help save costs related to engineering new T-cells every time the cancer mutates. Typically CAR-T cell therapy costs several hundred thousand dollars, if the same set of T-cells can be reused with new targets, it will help greatly reduce the cost of treating cancer using T-cell therapies. 

Overall, this is a very good advancement and can potentially help treat cancer far more effectively while simultaneously making these treatments more accessible. Although like all technology we discuss in this newsletter, it still needs more testing.

Read the full paper:

• Nature

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Featured Fake News

Yeah, this is fake. 

The claim originates from a typical fake news website which has grossly misinterpreted an actual UN report calling for age-appropriate sex education. 

As we’ve discussed before, age-appropriate sex education is a progressive policy and it can most easily be seen in action in the Netherlands where applying such a system to public education strongly correlated with a decrease in teen pregnancies, more responsible and safer sexual practices, and most people finding their first sexual partners at an older age. This is very different from the abstinence focused sexual education in the United States. 

Make no mistake, here at Unmasking Medicine we are not advocating for it to be imposed everywhere as there are very real challenges. We are just saying that the above claim is false. 

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HIV Drug Could Treat Dementia?

HIV Drug Could Treat Dementia

Recently scientists found that a long approved drug by GSK to treat HIV might have the potential to treat dementia and Hungtinton’s disease (HD). The researchers tried using the drug on mice with dementia and HD and found that it reduced the amount of misfolded proteins that are involved in the diseases. 

Dementia is technically a symptom of many diseases and is mainly associated with loss of memory and cognitive decline and HD is one such disease that has dementia as a symptom. You may have heard of the tau protein before as the leading theorized cause of Alzheimer’s, in fact, in many diseases under the dementia umbrella it is the known protein whose misfolding is most closely correlated with the disease's progression. This is also true in the case of HD.

With the HIV drug, the scientists were able to show that mice treated with the drug have lower levels of misfolded tau protein compared to their untreated counterparts. The reasoning here was that dementia affected mice that had a receptor called CCR5 knocked out showed lower buildup of the tau protein. CCR5 is expressed on many types of immune cells but knocking it out can help microglia can help them respond to dementia better. The HIV virus can bind to CCR5 and the drug that was used in these experiments works by blocking that binding. So it was reasoned that blocking CCR5 in microglia can help treat dementia and HD. 

The scientists found that this was indeed the case and blocking CCR5 allowed microglia to clear misfolded proteins with greater efficacy. However, there is a lot more that still needs to be studied before taking the drug forward for this second application. Since CCR5 is expressed on many types of immune cells, it is possible that this may have several other side effects. However, since the drug is already approved for clinical use in the context of HIV, it is already shown to be safe and expanding the use case of an already approved drug is far easier than developing a completely new one.

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California Approves $150M in Emergency Loans for Struggling Hospitals

California lawmakers have approved legislation granting $150 million in interest-free loans to financially distressed hospitals across the state, with additional support expected to be included in the state’s upcoming budget. The Distressed Hospital Loan Program, established under AB-112, aims to support non-profit and public hospitals that are struggling to stay open or reopen after closure. Governor Gavin Newsom is expected to sign off on the bill, which has the potential to impact healthcare facilities across California.

Governor Newsom has instructed the State Departments of Health Care Services and Public Heatlh to “develop a metholody” to target facilities that are small, rural, critical access hospitals, or those treating a disproportionate share of Medicaid patients. The intention is to exclude hospitals that are part of a system with more than two hospitals, investor-owned hospitals, and freestanding inpatient psychiatric hospitals. The loans are to be repaid within six years, with monthly repayments commencing 18 months after the loan is received.

The necessity of these loans arises from the ongoing financial struggles faced by many such hospitals and healthcare facilities in remote areas post-pandemic. Without financial assistance, these hospitals risk closure, and that would leave their communities without access to crucial healthcare services.

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Featured Fake News

You know what. We did not see this ourselves but it was brought to our attention and we wanted to share it with you.

Enjoy this fake news. It’s a good one haha…

Reuters

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A New Drug Class: RNA Degraders | Aerofarms leafy greens producing vaccines?

Image Source: Shutterstock (RNA) | Edited by: Janey Yee @ Unmasking Medicine

A New Drug Class: RNA Degraders

Researchers at the University of Cambridge have developed a new class of drugs that can degrade the RNA of the COVID-19 virus and thus reduce viral loads. These small molecules called proximity-induced nucleic acid degraders or PINAD can target RNA sequences and degrade them, preventing the formation of the protein they were meant to make. In the case of COVID-19 RNA, this degrader prevents the virus from using our cell’s machinery to make more copies of itself. 

Degrading RNA is seen as an alternative way to treat disease, typically most therapies target the proteins of a disease, such as but not limited to antibody treatments, to treat a disease. However, if one could successfully destroy the RNA that is supposed to make the protein, they would be able to stop the disease one step earlier. This is important as targeting proteins will often lead to the protein’s sequence mutating and therefore changing its shape and thus evade the treatment. In the case of RNA, mutating the sequence will be a bit harder if a conserved sequence is targeted. Conserved sequences are usually important for basic function and therefore don’t often successfully mutate. 

A problem with targeting RNA has been that an enzyme called ribonuclease is needed to do the actual degrading and most small molecules that are used as potential treatments are only able to call the ribonuclease to a target sequence to do the work which limits efficacy in cell types that do not have a lot of ribonuclease. In the case of PINADs, this small molecule can do the degrading itself which makes it so much more promising. 

So far the researchers have been able to show that this idea works well in mice models for COVID-19 and they are now going to test PINADs in the context of other diseases and further test their COVID-19 treatment. This is a pretty promising technology since it can make RNA targeting therapy a reality which will open a lot of avenues for treating disease, especially in cases wherein targeting diseased or a disease’s protein(s) are not feasible. 

Read More:

• Fierce Biotech

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Featured Fake News

This week instagram shorts and tiktoks have been circulating the claim that the company Aerofarms is selling COVID-19 vaccine containing foods through Whole Foods. 

This is completely false for many reasons. Firstly, Aerofarms did grow protein producing plants for COVID research, but they did not grow the mRNA vaccines. 

To clarify, when we discuss proteins in this context we are referring to the product of one or more chains of amino acids, which is more broad than the protein most people are used to hearing about in nutrition values.

The protein Aerofarms was producing was the ACE-2 receptor. Basically, they were creating a plant that could be infected with COVID so they could study COVID infections without having to infect humans or rats. They did not produce a vaccine (UPenn researchers did use it to produce a covid trapping chewing gum though).

However, it is true that they are researching how they can use plant engineering to produce protein based vaccines. These are a specific type of vaccine, and while there is one for COVID-19 in the works, it is not available yet because they take much longer to develop. To see the different types of vaccines, please check out the following graphic from nature.

A second reason why this claim is false is because we do not have any edible vaccines. NONE. The chief reason being it is incredibly difficult for vaccines to survive through the amylase in our saliva and all the acid and digestive enzymes in our stomach and then entering our blood stream somehow through the small intestines. As far as our current technology goes, it is impossible. Even among pathogens, there are very few bacteria and viruses that can infect our digestive tract or use our digestive tract to enter the body because they get broken down. Hence, most stomach bugs tend to be parasites.

Most bacterial and viral infections infect us through open wounds or our respiratory system for these reasons. The same logic applies to the incredibly small molecules that make up vaccines and why we need to inject them directly into our bloodstream.

Now, you may be wondering how other drugs can be ingested but not vaccines. The reason for this is that nearly all ingestible drugs have zero biological macromolecules like carbohydrates, proteins, lipids, and nucleic acids. Hence, why our digestive tract does not have anything to digest them, because they are totally useless for building new cells in our bodies. Vaccines on the other hand, tend to have these biological macromolecules so our digestive tract does digest them and turn them into raw material for new cells. 

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Language Models For Healthcare & CRISPR for Cows

Read about how generative language models could transform healthcare and CRISPR can be used on cows to curb greenhouse gas emissions

Generative Language Models Transforming Patient Care

Tech giants and startups alike are eagerly exploring the potential of generative AI tools in medical settings, with Google recently announcing the release of its medical large language model (LLM), Med-PaLM 2, to a select group of users. LLMs, for those unfamiliar, are AI tools that specialize in understanding and generating language. Med-PaLM 2 has been developed specifically for the medical domain, aiming to provide more accurate and safe answers to medical questions.

This move by Google comes on the heels of Microsoft's own foray into generative AI tools for healthcare, with the release of a new Azure Health Bot template. As these tech giants continue to innovate, it's clear that the race is on to harness the power of generative AI in the medical field. Google has been working closely with clinicians and non-clinicians alike to assess Med-PaLM and Med-PaLM 2, focusing on aspects such as scientific consensus, medical reasoning, knowledge recall, and potential harm. In addition to Med-PaLM 2, Google has also introduced new AI-enabled tools to streamline health insurance prior authorization and claims processing. These tools transform unstructured data into structured data, allowing experts to make faster decisions and ultimately improving access to timely patient care.

Doximity, a digital platform for medical professionals, has joined the race as well, releasing a beta version of a ChatGPT tool for doctors. This tool assists with time-consuming administrative tasks, such as drafting and faxing preauthorization and appeal letters to insurers. Abridge, a startup providing AI-powered medical transcription services, has deployed one of the largest generative AI projects in healthcare to date. The University of Kansas Health System has implemented Abridge's tools to assist over 1,500 physicians across more than 140 locations. This technology listens to patient-doctor visits and smartly summarizes key parts of the conversation for both parties.

Despite the enthusiasm surrounding generative AI, caution is still advised in its application within healthcare. The technology can sometimes "hallucinate" or invent a response when it lacks sufficient information. However, a recent survey by Huma.AI reveals that 86% of medical affairs leaders believe generative AI can be applied in life science companies. Generative AI has the potential to transform medical affairs activities, enhance engagement with healthcare professionals, and ensure products are used safely and effectively. It's important to keep in mind, though, that generative AI is not meant to replace human expertise but to augment and support human decision-making.

The recent surge of interest and innovation in generative AI within the medical field highlights the potential for significant advances in research and patient care. As tech giants and startups continue to develop and refine these tools, it will be crucial to strike a balance between the capabilities of generative AI and the need for human expertise in healthcare. The ultimate goal is to create a more efficient and effective healthcare system for all.

Source:

Fierce Healthcare

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CRISPR on cows

Cow burps are responsible for over 27% of the methane that is released into the atmosphere as a result of human activity. When cows digest food, the microbes in their guts convert grass or hay into energy and release methane as a byproduct. The sheer number of cows that humans raise for beef, milk and other dairy products makes cows a major source of greenhouse gasses especially considering the fact that methane traps 25 times more heat than carbon dioxide.

With the advent of CRISPR, a gene editing technology that allows scientists to alter the genome of an organism by adding or removing DNA sequences, an exciting opportunity has opened up to explore the use of CRISPR in trying to genetically alter cows to make them produce less methane. 

CRISPR has been around for some time and used in labs and on cells that are grown in dishes, there are some small animal use cases and clinical trials but CRISPR has not been used in non-controlled environments yet. Additionally, it is difficult to get the CRISPR machinery into bacteria, in a lab you can give bacteria an electric shock and get the CRISPR machinery inside of it but you can not do that when the bacteria is in a cow. 

This is one of the big challenges that scientists at the Innovative Genomics Institute are working towards addressing. They need to find a way to get the CRISPR machinery inside the bacteria in a cow and also find appropriate genetic modifications to reduce how much methane bacteria in the gut microbiome produces. People have been able to use viruses as delivery vehicles for CRISPR in plants and bacteria but this is usually done in a pure colony of one bacteria and not a mixed population like what you would have in the gut microbiome. 

Ideally, it would be a sort of pill that can be given to the cow when it is a calf and have a permanent modification in the calf so that a repeat dose or repetitive dosing is not required in the future. This is an exciting area of research and if successful can help us curb one of the biggest sources of greenhouse gasses.

Source

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Featured Fake News

After nearly 5 months since Dr. Fauci officially retired from the position of Director of NIAID, social media users have started circulating the claim that we have zero new COVID-19 strains since his retirement. 

First of all, that is not true. The current strain which accounts for >80% of COVID-19 cases and the most transmissible strain to date was already spreading rapidly while Dr. Fauci was starting his retirement. Additionally, on March 30, 2023 WHO announced a new omicron sub lineage of interest currently called XBB.1.16.

Secondly, it is impossible for new variants to stop showing up unless the pathogen goes extinct. That is just how biology works. There will inevitably be mutations in the viral genome as they are replicated which will give way to new variants. This is true for both real organisms and laboratory engineered ones. 

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Mifepristone Shakes the Abortion Landscape

Editor’s Letter

Dear readers,

I would like to apologize for the skipped postings these past 2 months. The articles were written both of the times that we skipped posting, but I neglected to schedule the newsletter and did not realize it until the middle of the week. Going forward, I am going to set more alarms and aim to schedule the newsletter earlier so that there will not be any more skipped weeks.

Sorry again,

Shean Fu

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Mifepristone Shakes Abortion Landscape with Conflicting Rulings

In a groundbreaking decision, a federal judge in Texas has suspended the FDA's approval of the abortion drug mifepristone, but delayed implementing the ruling to give the Biden administration time to appeal. The decision could have far-reaching consequences on medication-assisted abortions, particularly as the drug has become increasingly important since the Supreme Court overturned Roe v. Wade last year.

Simultaneously, a federal judge in Washington state ruled that the FDA must continue to supply the drug in 12 liberal states that sought to expand access to mifepristone. This ruling, however, only applies to the 18 states that sued.

U.S. District Judge Matthew Kacsmaryk sided with the anti-abortion group Alliance for Hippocratic Medicine, which argued that the drug's approval in 2000 was rushed and that the agency neglected requests for judicial review. The Department of Justice, President Joe Biden, and Danco Laboratories (which manufactures mifepristone) all signaled their intent to appeal the decision.

If the suspension of the FDA's approval goes into effect, mifepristone would no longer be available in the U.S., leaving only surgical procedures or off-label use of misoprostol as options for terminating pregnancies in states where abortion is legal. Misoprostol, not affected by the injunction, is not FDA-approved for terminating pregnancies on its own, and the one-drug approach has been shown to be less effective than the two-pill regimen.

The Alliance for Hippocratic Medicine sued in November, claiming the government inadequately assessed the drug's safety and should not have made it accessible via telehealth during the pandemic. They sought an injunction to halt the use of mifepristone nationwide while the case plays out.

The case could ultimately be decided by the Supreme Court, testing the Court's pronouncement last summer that it was leaving the issue of abortion to states and other branches of government to decide as a policy question. The votes of Justice Brett Kavanaugh and Chief Justice John Roberts, who voted against overturning Roe, could be crucial.

Reactions to the decision have been mixed. Vice President Kamala Harris stated that the ruling undermines the FDA's ability to approve safe and effective medications based on science, not politics. Erik Baptist, senior counsel for the Alliance Defending Freedom, called it a significant victory for doctors, medical associations, and women's health and safety. Nancy Northup, president and CEO at the Center for Reproductive Rights, disagreed, saying the decision "has no basis in law or fact."

The lawsuit alleges that medication abortion has potentially serious and life-threatening effects, but studies have shown that when mifepristone and misoprostol are used together under doctors' supervision, the regimen successfully terminates pregnancies up to 99.6% of the time and has a 0.4% risk of major complications.

The FDA has argued that it extensively reviewed the scientific evidence and determined that mifepristone's benefits outweigh any risks. It also called the lawsuit "extraordinary and unprecedented." There is little legal precedent for a court to overturn an FDA approval of a drug.

Sources:

Fierce Healthcare

NBC News

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Image Source: ehealthbulletin.com | Edited by: Janey Yee @ Unmasking Medicine

Solving The Puzzle Of How Cells Select Their Identity

It is well known now that stem cells formed during human development have the ability to become any cell in the body, but how do these cells know what type of cell to form? Now that is a much bigger mystery. We know that all cells have the same DNA and therefore a muscle cell has the same DNA as a cell in your brain but clearly they express different genes which gives them their unique forms and functions. 

Our understanding of how every cell knows what to do has been quite limited so far. We previously identified Hox genes and determined that they helped define what area of the body is to become what (like limbs, torso, etc). More recently though, we’ve discovered polycomb proteins complexes. These proteins restrict the set of genes a cell can access and thus serve as a mechanism to restrict cells from expressing genes that they are not supposed to, for example, a heart cell should not be making antibodies, which is a function of a B-cell. 

At the Trinity college in Dublin, researchers added to this body of knowledge and found that polycomb complexes can be used as a way to treat cancer, specifically PRC1 and PRC2. There are two forms of PRC2 but they have the same function, so the need of two different proteins to do the same function has been a puzzle to scientists. The researchers were able to finally answer that question, PRC2 has two forms because it has to recruit two different versions of PRC1 in order to function. 

This discovery is very important in understanding how the mechanics of these proteins and therefore, how mutations in them can lead to cancer. The easiest way to envision this would be a non-functioning PRC which allows a cell to express a gene it shouldn’t be expressing. 

There is still a long way to go in developing a therapeutic application that exploits this mechanism and perhaps stop the expression of cancer causing genes but now that we have a basic understanding of it, we can start working towards harnessing it as a therapeutic method. 

• Fierce Biotech 

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Featured Fake News

In a clip posted on Instagram a bio-energetic chiropractor (we have no idea what that means) claims that annual mammograms for a 10-year period expose patients to Hiroshima levels of radiation.

This is completely false. According to a paper in the Journal of Breast Imaging titled “Radiation Doses and Risks in Breast Screening” mammograms expose patients to 0.36 millisieverts (mSv) per screening. According to the author of the paper, annual screenings over 10 years is in fact, just 10 times that amount, something anyone should be able to calculate with basic arithmetic.

Therefore, a total of 3.6 mSv is how much radiation a patient would be exposed to, and this is over the course of a decade, unlike an atomic bomb. In the 1-mile radius of the atomic bomb dropped on Hiroshima the radiation dosage was between 2250-2530 mSv. 3.6 mSv over 10 years  is not comparable at all.

However, even if you are in the camp that no radiation is better than some radiation, you should know that mammograms are the most highly correlated reason behind the reduction and in breast cancer deaths.