Can we re-grow cartilage in damaged knees? A new Stanford study offers hope

Knee pain is one of the most common afflictions among athletes and among older people in general. I’ve written about treatments for knee pain before, specifically about the many so-called alternative therapies that just don’t work.

(Quick review: the supplements glucosamine and chondroitin don’t work. Injections of hyaluronic acid don’t work. Acupuncture really doesn’t work. Simple pain relievers like ibuprofen work, but only for a short time.)

The problem is that cartilage, which provides a cushion between the large bones of the upper and lower leg, doesn’t regenerate itself. When you have cartilage damage, either from an injury or just wear and tear, you lose that cushion and you get pain and inflammation. Because the cartilage doesn’t really heal, if the damage gets severe, you might eventually need a knee replacement.

There is hope, though. For years now, I’ve been following stem cell research to see if it offers the promise to truly regenerate cartilage (or any other tissue, for that matter). Stem cells are special types of cell that can generate all of the different cells in our bodies, from blood cells to heart cells to lung cells to cartilage. Back in 2006, scientists made a major breakthrough when they discovered how to turn normal cells back into stem cells. Ever since, scientists have been exploring how to turn stem cells into just what we want them to be.

To repair damaged cartilage, what we’d really like is fresh new cartilage grown from our own stem cells. This is what a new study out of Stanford University, just published in the journal Nature Medicine, promises to do.

Here’s how it works. It turns out that the ends of our leg bones do contain stem cells, and if the bones are damaged, those stem cells will create new cells in response. The problem is that the new cells are basically scar tissue, not cartilage. The scar tissue wears out pretty quickly, and doesn’t provide the cushioning that cartilage does.

Stimulating the stem cells to get started is easy, if a bit crude: orthopedic surgeons already do this by drilling very tiny holes in the ends of the bone, a technique called microfracture. This provides some pain relief when the scar tissue appears, but it’s only temporary.

The Stanford team, led by Matthew Murphy, Charles K.F. Chan, and Michael Longaker, decided to use some of the latest findings about stem cells to steer the cells in a different direction after microfracture surgery. They did this by adding two proteins to the ends of the bones. The first one was BMP2 (bone morphogenetic protein 2), which encourages the stem cells to make new bone cells. They also added a second protein, VEGFR1 (vascular endothelial growth factor), which halts the process of bone formation in a way that leaves cartilage instead.

What’s exciting about this therapy is that it actually worked! New cartilage grew from the stem cells, and it appeared to reduce pain. The big caveat here, and this bears emphasis, is that the experiments were done in mice–and many studies that work on mice fail to reproduce in humans. Recognizing this limitation, the Stanford team also conducted experiments using human cells that had been transplanted into mice, showing that the treatment did indeed create human (not mouse) cartilage.

Next up will be studies in humans, to see if this works as well in people as it did in mice. If it does, another big advantage, as Prof. Longaker pointed out, is that both BMP2 and VEGF have already been approved by the FDA for other uses. This should make it easier to get approval for the new treatment as a therapy for aching knees. He suggested that, eventually, doctors might:

“follow a ‘Jiffy Lube’ model of cartilage replenishment. You don’t wait for damage to accumulate — you go in periodically and use this technique to boost your articular cartilage before you have a problem.”

So when can we get this new cartilage-healing treatment? More studies will likely take years.

Well, as Dr. Robert Marx pointed out in the NY Times, there’s nothing to stop orthopedists from trying this treatment out right away, because the drugs required are already on the market. Thus long before we see convincing evidence that it works in humans, doctors might be trying this out. For a patient who has deteriorating cartilage, if given the choice between waiting many years to see how the studies turn out versus trying a promising new treatment right away, the temptation might be too great to resist.

This is where things get tricky. There are already numerous orthopedic practices offering “stem cell therapy for knees” along with “platelet-rich plasma,” which they will inject right into your knees (for a price, of course). It took me less than 30 seconds of Googling to find dozens of practices offering these therapies, with assurances that they “repair the knee naturally ... by stimulating the creation of cartilage.” Note that these clinics are not using the new Stanford technique (not yet, at least), and there’s no good evidence that these injections will re-grow cartilage, despite the testimonials on many websites. So for anyone looking for knee pain treatments, caveat emptor.

Let’s hope this new treatment method works. For those of us (including myself) with aching knees, this new therapy is the most promising one I’ve seen in a very long time.

Some odd truths about viruses, and about the COVID-19 viruse

The virus that has devastated the world this year, SARS-CoV-2, is not a living organism. Viruses are not alive. Think of them instead as biological machines, incredibly small ones.

What, exactly, is a virus? Many people outside the world of science and medicine don’t really know, so today I’m going to describe just a few of their essential features.

Viruses have, in general, just two functions: they invade your cells, and then they borrow your own cells’ machinery to copy themselves. (Note: for simplicity I’m describing viruses that infect humans, but in reality they infect pretty much every living thing, from bacteria to plants to animals.) After making many copies, they break out, usually destroying the cell they’ve invaded, and do it again.

Here’s a weird thing about viruses. All living things on this planet are made from instructions encoded in DNA. Some viruses are also made of DNA, but many are made of RNA instead. RNA is a lot like DNA, but it doesn’t have that famous double-stranded helix structure; instead, it’s just a single strand.

Now consider how small they are. The Covid-19 virus, SARS-CoV-2, has just 29 genes that are encoded in just under 30,000 letters of RNA. Other viruses can be even smaller: the influenza virus has just 10 genes, encoded in 13,588 letters of RNA. In contrast, the human genome has about 3 billion letters of DNA, and over 20,000 genes. In other words, our genome has 100,000 times more information encoded in it than the Covid-19 virus.

And yet these simple machines with a handful of genes can destroy us. Think of it like throwing a wrench into a running engine: the wrench is simple, but that doesn’t mean it can’t gum up the works of a far more complicated device. So too with viruses and their hosts.

It’s not just that they have a small genetic code: viruses are also physically small. So small, in fact that they cannot be seen under a normal microscope. Bacteria are huge compared to viruses; in fact, bacteria suffer viral infections just like humans do.

(Aside: the exciting new technology known as CRISPR is actually a mechanism created by bacteria to fight off viral infections!)

One consequence of virus’s tiny size is that when the 1918 flu pandemic swept the world, no one knew it was caused by a virus. Scientists didn’t have the technology to see a virus at that time. The influenza virus–the true cause of flu–wasn’t discovered until 15 years later, in 1933.

(Another aside: a bacterium called Haemophilus influenzae was given its name because scientists thought it caused the flu. It doesn’t. It does cause ear infections and sometimes-deadly meningitis, though, and for that reason the Hib vaccine, which prevents infection from this bacterium, is a critical part of the childhood vaccine schedule.)

Another odd fact about viruses: they’re not cells. They don’t have a proper cell wall, as such, just a shell made out of a few proteins. The shells encapsulate the tiny genetic code of the virus. We call them “particles” for lack of a better word.

Viruses are everywhere, and they are far more numerous than bacteria. Bacteria, in turn, are far more numerous than plants and animals. Viruses are also devastatingly effective at what they do (infecting living cells and hijacking those cells to make more viruses), which is why we will never rid ourselves of them.

While we can’t get rid of them, we can fight the viruses that cause human diseases like Covid-19. The best way to do that is to prevent viruses from invading our cells. How? There’s only one good way that we know of so far, and that’s to use the human immune system to fight them off at the molecular level. (While viruses are simple, the immune system is really complicated. I can’t possibly explain it here, but check out Ed Yong’s recent story at The Atlantic for an excellent attempt to de-mystify the immune system.)

This is where vaccination comes in. When a virus invades us, our immune system creates custom-designed cells (see that Ed Yong article) that recognize and destroy the virus. Then it becomes a race: if the immune system wins, it destroys all of the viral particles. If the virus overwhelms the host, the result can be fatal.

For Covid-19, most people mount an immune response quickly enough to avoid getting seriously ill. However, for those that don’t, the results are extremely serious. A vaccine works by “showing” the immune system part of the virus, but doing this in a way that isn’t actually an infection. One strategy used by several of the Covid-19 vaccines under development is to just package up one of the SARS-CoV-2 proteins, without the rest of the virus. The vaccine itself will prime the immune system to recognize the Covid-19 virus without actually causing an infection. Then, if that person is actually infected, the immune system swings into action quickly, and fights off Covid-19 before it ever gets established.

So that’s it. Covid-19 is caused by a tiny, sub-microscopic biological machine, a virus with just 29 genes. The virus can be ruthlessly effective, but our immune system can wipe it out if we give it the right clues. Let’s hope we’ll have a vaccine soon.

Disclaimer: the content on this site is my personal opinion and is independent of my affiliation with Johns Hopkins University.