Receptors – critical biological parts hijacked by viruses

“Receptor.” It’s yet another bit of biological jargon. It sounds like receptors should be small spacecraft launched to defend an alien mothership. Or maybe receptors are courtly underlings who receive guests before their presentation to the queen? In truth, receptors are cool and important biological structures that reside on cell surfaces.

As you might remember from my post on cell membranes, the layers of fat that surround cells are quite complex. They are studded with proteins that perform many functions. Some of these proteins are receptors.

Receptors all detect stimuli and cause cells to respond in some way. Often, receptors grab onto specific molecules floating nearby. Then they signal to the cell that they’ve done so.

The exact cellular response to a receptor signal depends on the receptor and on the stimulus detected. Some signals cause cells to grow. Others cause cells to move. Still others coordinate behaviors among many cells. Receptors are critical for many of life’s complicated processes.

Unfortunately, receptors have a darker side too. Many viruses use receptors as handles. With a good hold a on receptor, a virus can barge into a cell. Thus viruses hijack receptors to infect cells and cause disease.

Drawing of a virus grabbing onto a receptor to infect a  cell.
A virus grabbing onto a receptor to infect a cell.

Using receptor biology to prevent viral infection

Interestingly, scientists are using receptors to fight viral infections. They reason that, if they get rid of receptors used by viruses, the viruses will have no way of infecting cells. Many receptors are only important under specific circumstances. Thus, getting rid of them will have some small negative consequences, but the benefits of resisting viral infection are worth it.

Indeed, a scientist in China recently claimed to have modified babies to make them resistant to HIV (these are the so-called “CRISPR babies”). This scientist used a genetic technique to delete one of the receptors hijacked by HIV. The researcher performed this technique in embryos. Thus all the modified babies’ should be able to pass their modifications to their offspring.

What this scientist did was foolish for many reasons. Some of them include:

  • It is unclear if the technique was safe.
  • It is unclear if the technique accomplished its goal.
  • There are effective ways to prevent HIV transmission that don’t require this technique.
  • Some types of HIV use other receptors. Thus, the children won’t be protected from all types of HIV.

On top of all this, the scientist’s use of this technique raises many ethical questions. Most of these stem from the fact that the babies can pass on their human-designed modifications to their offspring. Should we modify the human gene pool in this way? Do we know enough about the potential consequences? Can we use similar techniques to do more than treat disease? Society at large must face all of these questions before we decide to use any similar techniques again.

This unfortunate work aside, other techniques modify receptors on adult cells. Future generations can’t inherit the modifications. Thus we can use these techniques following standard regulatory rules. Indeed, clinical trials using modified adult cells to treat HIV have had very promising results! Scientists can also give immune cells receptors that make them better at fighting cancer (see my previous discussion of CAR-T cells in this post). Receptors play a role in so many biological processes that we’ll likely see many more cool uses of them soon!

The next time you see a picture of smooth, round cell, remember that it’s studded with receptors and they do a lot!

Why Viruses Are Great Gene Delivery Vehicles

Drawing of a cartoon virus delivering a piece of DNAPretend that you’re a delivery person. Now pretend that you have all the packages you need to deliver today. You step out of your delivery truck onto the street. You’re ready to seize the day and start delivering with a smile on your face, but, just then, some crazed urge overcomes you. You want to do the worst job possible. How are you going to satisfy this urge?

If I wanted to be an absolutely terrible delivery person, I’d walk down the middle of the street and throw my packages everywhere at random. I’d probably end up throwing many packages into the street and into random yards. I’d probably hit some people and their pets. I might even get hit by a car. However, if I threw enough packages, at some point I might at least get one into the appropriate yard or driveway.

Like letters and packages, gene therapies need good delivery people. For gene therapies to work, healthcare providers need to successfully and specifically deliver genes to broken cells. Once in the broken cells, the genes produce things that help fix the cells thereby treating or curing disease. In a gene therapy for blindness for example, you might deliver genes to cells in the eye that make the eye better at detecting light (Connie Cepko’s lab at Harvard is doing this).

Unfortunately, if we just inject genes strait into our bodies, the gene therapy will function about as effectively as our crazed delivery person – they don’t necessarily get to the right place, they might be destroyed in the bloodstream, and they could cause further dangerous effects if they get into the wrong cells.

So what makes a good delivery person? A good delivery person carefully walks down the sidewalk (avoiding cars and stray dogs) and delicately places packages and letters into the mailboxes of their intended recipients. That’s all well and good for big ole letters and packages, but how do we go about delivering genes with such tenderness and care? Nature provides the answer – viruses!

Viruses as Gene Delivery People

You’re possibly looking at your screen a little skeptically and thinking, “Don’t viruses cause disease?” The answer is, yes they do, BUT, to cause disease, viruses often must deliver their own genes to cells. We now know enough about how some viruses work that we can strip them of their dangerous genes and, instead, get them to deliver therapeutic genes to cells.

Viruses are fantastic because many already deliver genes to specific cells (remember how HIV targets the immune system for instance). In fact, using our knowledge of how viruses work, we can even engineer them to deliver genes to new cell types.

Limitations of Viral Delivery

So, why haven’t we used viruses and gene therapy to cure a ton of diseases? Part of the answer to this question is that we’re only now beginning to understand enough about diseases, genes, and viruses to make effective therapies. In addition, viruses do have limitations. Here are a few:

  1. Size – Viruses are very very small (way smaller than cells) and just can’t deliver all the genes we need to treat some complex diseases. This is like having a delivery person who is too weak to deliver all of your new Ikea furniture even though you know it will look awesome in your new apartment.
  2. Lifespan – Some viruses deliver genes to cells and the genes do their jobs for a while, but then they stop working. This is something like your favorite movie going off of Netflix. It’s delivered to you for a while and you’re kept happy, but then you can’t watch it anymore for unknown reasons leaving you in pain.
  3. Immune Responses – Some viruses used for gene therapy still have markers that tell the immune system that they’re dangerous. These can cause immune reactions that harm the patient. This would be like your delivery person dealing drugs on the side and getting confronted by the cops at your doorstep… you might get hurt in the exchange.
  4. Integration Problems – Though some viruses are very good at getting therapeutic genes into cells, sometimes they put them in the wrong place or they put some of their own genes into the cells leading to further damage and disease. This would be like your delivery person occasionally jamming a package down your toilet without you noticing or accidentally dropping his pet cobra in your mailbox.

Different types of virus-based gene delivery systems have different combinations and levels of these limitations (some of the advantages and limitations of viruses used in research are discussed in this guide). It is therefore up to researchers to pick or engineer the right viruses to reduce these limitations for specific diseases.

Excitingly, we’ve learned a ton about how viruses work and you’re likely to see many virus enabled gene therapies coming out soon. Heck Voyager Therapeutics recently described promising results from their work developing a virus delivered gene therapy for Parkinson’s disease. So keep your eyes open – I’m sure there’s much more to come!