A dark era for reproductive rights
Plus how drugs work, why cancer is hard, a standing ovation for a cancer trial, the origin of the Black Death, another failed Alzheimer's drug, and a small successful trial for cancer.
Friends,
This newsletter focuses on “science and society”. I’ve never shied away from talking about the broader effects and outcomes of either COVID-19, or vaccine inequality, or climate change on parts of society. Science is not objective and it cannot be because it is conducted by humans who are not objective. We live in societies among other people. We are affected by them and what we develop in the lab has ethical outcomes.
There is no other way to say this. Earlier this week, the curtailing of reproductive rights of women by the U.S. Supreme Court was one of the darkest days in the modern history of America. It was a regressive and medically unsound move that codifies treating women as inferior to men, by taking away one of the most personal decisions a person can make. It removes individual choice and agency. And it is a matter of science.
Regardless of what your own views are on abortion, they are your own views. You and I have no right to impose our views on anyone else. And if we are men who do not bear fetuses into birth, then we have less right to say anything. This is a matter of respecting choice of a human who is an equal in society and alive today to make the best decision for herself and for her family.
I’m not alone in saying this.
In polls, by a margin of more than two to one, adult population of the U.S. actually agrees that women should have a choice in their lives.
Broadly, this ruling a huge blow for the credentials of the US — and for the separation of church and state. A narrow Christian reading of the Bible has now trumped the fundamental protection of human values for all. The Supreme Court has now ruled that it does not matter what you believe in in terms of individual liberty.
The Supreme Court has ruled what a bunch of white slaveholding Christian men wrote over 200 years ago in a foundational document is sacrosanct and immutable. It takes precedence over the real considerations and health of millions of living women.
I know there are a lot of immediate reactions to the Supreme Court ruling online, but if you listen to one though investigative podcast on how we got here and where we go next, make it this one.
Now, on to other news.
Another Alzheimer’s drug failure
In my last newsletter, I focused on Alzheimer’s disease and how we’ve missed the point on this particular kind of dementia from its first discovery over a 100 years ago. Desite afflicting over 23 million people worldwide and billions of dollars spent in trying to find a cure, there is none.
I mentioned that the problem results from focusing on one idea— the amyloid theory — that posits that Alzheimer’s disease is caused by the buildup of certain kinds of deposits in the brain. The idea has been that if you remove the deposits, then clinical symptoms will get better. But this has not borne out in actual patients
Another line of thinking has been that the deposits need to be removed before patients suffer from Alzheimer’s — that we’re treating the disease too late in people who have deposits and that’s why drug trials are failing.
Roche set out to test a candidate drug using this strategy. They identified a family in Colombia that had a rare genetic variant that made adults prone to very early onset dementia. The idea here was that giving the drug for many years would prevent the buildup of these deposits before Alzheimer’s struck thus validating an early treatment approach for the disease.
The bottomline is that the drug trial failed and this is another setback for Alzheimer’s patients and for the prevailing hypothesis.
Alzheimer’s disease is likely to have many risk factors and causes.
The wisdom that prevailed for decades that getting rid of amyloid deposits will cure the disease is not likely to work.
Fantastic results from a small cancer trial
I wrote about a rectal cancer trial that made the news in a recent column for Hindustan Times.
Before I get to that, I want to recap briefly how a drug actually works. This is modified from another column I wrote on cancer drugs last year.
How does a drug actually work after you swallow it?
Most drugs are small chemical molecules that enter the bloodstream and then find their way to a biological target in your body. If you have taken an antibiotic, then the target is part of bacteria. If you have taken a pill for fever, headaches, or blood pressure, for example, the target is part of your own body.
The targets of drugs are usually proteins. Proteins are biological machines that perform all kinds of jobs in the body. Sometimes proteins start doing weird things. Some of this can be attributed to small changes (mutations) in the blueprint of how they’re made. The blueprint that describes the configuration of a protein is a stretch of DNA called a gene.
How a protein works is determined by its shape. If a protein could be scaled up to the size of a person, then most drugs would typically be the size of a marble. What a drug does is that it zeroes in on an important part of the target protein where it can stick and then it modifies the way the protein works.
The first generation of drugs were created without any knowledge of the biology of how they attached to proteins; people just observed what happened when they tested them in animals and in people. The second generation of drugs contained changes to existing natural products isolated from plants and microbes that made them work even better. The newest generation of drugs targets proteins and tries to fit their shapes like small pieces of a puzzle.
There is also a brute force approach in which a target is bombarded with a “library” of millions of already created small molecules to see what sticks, and then this candidate drug is tweaked while testing in human cells. All these processes can take decades, and most candidate drugs don’t make it to the market at all.
Your genome contains over 20,000 protein-creating genes. Some proteins are abnormal in diseased states. But around 85% proteins are considered “undruggable” because scientists haven’t been able to get any candidate drug to stick to them well. That leaves around 5,000 that are druggable. Fewer yet (roughly 2%) actually have a drug that works on them. So, currently there are only around 500 proteins in the body that are targets for drugs for human diseases. Considering the wide range of human diseases, this number is small. Most of these proteins belong to only five families categorised on what they look like and what they do.
Sometimes, when scientists come up against a pesky protein that they can’t get a drug to stick to, they try to find alternate targets. Other times, the stakes are too high, and they continue toiling away in hope of a breakthrough.
Now, on to the current trial.
Why is cancer so hard to beat?
Cancer is a constellation of over 100 different diseases. It’s affected our ancestors even before they were human. It is evolution in real-time. It is so ubiquitous that you can study processes of cancer development. in single-celled yeast.
I’ve lost people to cancer. I’ve attended cancer conferences. I’ve written about it for science journals and in the popular press. The arc of cancer treatment is long. There’s never going to be one cure. But certain developments (like this one) move the entire field forward.
All cancers are essentially genetic diseases. That doesn’t mean that all cancers are inherited (though 5-10% of cancer patients have inherited gene variants that made them more susceptible). It means that cancers result from genes gone wild.
Why precision medicine is exciting
If you know what genes variants are likely to put you at risk of cancer you can try to prevent it. This was the first paradigm of precision medicine and it’s been in effect with greater successes for over two decades now. But you need to be able to treat cancer if it occurs too.
Treating diseases based on their specific traits is the second paradigm of precision medicine. And nowhere does this have greater promise than in cancer research. And this is the bit that’s excited me the most for the last two decades. And worth watching in the future.
Here’s a brief summary of the rectal cancer trial (and some limitations):
Treatment of advanced rectal cancers typically includes radiation therapy, chemotherapy, and surgery. This treatment method combining three approaches has resulted in high survival and cure rates for non-metastatic rectal cancer of up to 77% in three years.
But while a patient’s life may be saved, there is often a permanent toll that results in diminished quality of life. Many clinicians will, therefore, start with radiation and chemotherapy and assess how cancer is being managed, and then resort to surgery if needed.
I mentioned that cancers can arise from cells breaking down various checkpoints. Around 5 to 10% of patients with rectal cancers are deficient in one key cellular machine known as DNA-mismatch repair enzymes which are supposed to fix mutations. These patients don’t respond well to only radiation and chemotherapy, and so they often require surgery. And these are the patients who gave their consent to be a part of this experimental trial.
In the peer-reviewed medical article, results for 12 patients were reported, but in some media reports, there’s mention of up to 6 other patients who also benefited from this treatment.
Patients received dostarlimab, a monoclonal antibody to treat the specific molecular defect (mismatch repair) implicated in their cancer. Immunotherapy (instead of the standard radiation and chemotherapy) proceeded for six months.
Patients were routinely assessed by imaging with the plan to start radiation and chemotherapy if cancer was detected. So far, those treatment options have not been needed.
All of the patients had resolution of clinical signs: around a year later, cancer had not been found in a single patient who received dostarlimab.
Although these results have been presented as a “cure” it is still too early to say if cancer is gone in any of the patients who were treated with dostarlimab. Cancer is unpredictable and control of cancer after a year isn’t a guarantee that it won’t come back. Patients will need to be followed for much longer.
The trial size was also small. Larger trials with more diverse populations of patients will provide information on the efficacy of dostarlimab in larger groups. Patients responded well to immunotherapy, but long-term toxic effects in broader populations will also need to be documented.
The human gastrointestinal tract also contains diverse microbes, collectively called the gut microbiome. It is known that the gut microbiome influences the progression of rectal cancer, but it also might affect how well immunotherapy works. Not much is known about the interplay of gut microbes and biologics like monoclonal antibodies. More work on this front is needed.
Right now, there’s also the question of the cost of the treatment itself and the availability of the tools to diagnose mismatch-repair deficient rectal cancer outside of large cancer hospitals. This is certainly a concern in a country like India…
Dostarlimab is a monoclonal antibody that is used to treat endometrial cancer with mismatch-repair deficient cells. In the current trial, it has shown effectiveness with the same deficiency in cells for cancer at another location.
Mismatch repair deficiency has also been found in other kinds of gastrointestinal cancer, and also in some cancers of the prostate, bladder, breast, and thyroid. It’s tempting to speculate that we could use this drug for some cases of other cancers as well.
The take-home message is clear. We are getting better at treating cancers more effectively and with fewer adverse effects, based on their precise hallmarks. This is a shot in the arm for precision medicine.
A standing ovation for a cancer trial
(Courtesy, NCI)
Picture the plenary hall of the world’s leading cancer conference where over 20,000 doctors, scientists, and pharma company employees have descended. Cancer is a devastating disease and so standing ovations are rare. The American Society for Clinical Oncology meeting in Chicago just witnessed such a rare event — the first standing ovation since clinical reports from Herceptin in 2005 (according to STAT news). Two friends who were at this meeting also reported the rarity of this event.
The results of this trial was concurrently published in the New England Journal of Medicine.
This practice-changing trial hardly made the news. So what’s the big deal?
The trial represents progress in treating some of the most difficult cases of metastatic breast cancer. Around 55% of patients with advanced breast cancer may benefit.
Trastuzumab deruxtecan is a treatment option that was previously indicated for other forms of breast cancer. In this study it’s been shown to increase quality of life and lifespan in patients with metastatic HER2-low breast cancer, which was previously much harder to treat.
The molecule is known as an antibody-drug conjugate which packs a one-two punch to cancer cells.
The drug is not a cure and that’s why I suspect it flew under the radar (except among doctors and scientists who understand its real clinical potential).
What I’ve read
This is not an economics or finance newsletter. You all know there are too many of them already. ;-)
But as much of the world heads towards the next recession I can’t help but share a great book I read recently that explains economic cycles in very broad terms for those of us who are interested but have never taken a macroeconomics class.
Dalio is a famous billionaire hedge fund manager so he was able to enlist an army of researchers to scour data. But he writes very simply in broad terms.
If you’re too busy to read the book there’s a a series of YouTube videos too.
What else I’ve read
The most devastating pandemic in history might have originated in Kyrgyzstan.
China’s scientific research output is growing at a remarkable pace.
Some cancer cells wreak havoc while people sleep.
Genome of man from Pompeii sequenced.
Endnotes:
Maybe you saw a famous Korean streaming show and thought “whoa they’re eating a brick of raw instant noodles like I did when I was a hungry kid”.
Let me assure you that it’s a legit Korean snack complete with flavor packet. These are noodles you smash and eat, not boil which I discovered at my local Korean grocery store.