'The question that keeps me up at night.' A Boston researcher's quest to understand how platelets are made.

Without platelets, we would die pretty easily. The microscopic plate-shaped structures in our bloodstream rush to the site of an injury, forming clots that stop blood loss and help stimulate the growth of new cells. Platelets mean a healthy person won't bleed to death from a minor cut. Without them, surgery would be impossible. For those with conditions that limit platelet production, platelet donation is as important as blood donation.

But, for all their importance, we don't know that much about platelets and how they're made — something that shocked Dr. Kellie Machlus, a Boston Children's Hospital researcher and assistant professor at Harvard Medical School.

This week’s edition of the Joy Beat is celebrating Machlus, for the work she’s already done in her field — which is quite a bit — and for all the work she will continue to do as a pioneer in an underexplored field. She joined GBH’s All Things Considered host Arun Rath to share the joy she finds in her work and the unanswered questions to which she devotes her time. What follows is a lightly edited transcript. 

Arun Rath: When I was reading about this and getting ready for the interview, I was kind of shocked about how little we know about platelets. I thought that platelets were actually cells, but they’re not. They’re something that’s made by other cells.

Dr. Kellie Machlus: Okay, I’m really glad you brought this up. So they are made by megakaryocytes, which are very large cells in their bone marrow — but I would invite you to also consider platelets as cells. I think maybe that’s controversial, but platelets themselves are really, really dynamic.

They don’t have a nucleus, so people might say they’re not cells, but they do circulate in the blood, and they also activate. They contain these granules that get released. They change shape when they activate, they can translate and make protein. So I guess it’s kind of a unique thing that they’re made by one type of cell, and we consider platelets themselves also cells. So, totally OK to call a platelet a cell.

Rath: Wow. But it’s even more interesting the more that you talk about it because it can make proteins, so they do more than just form blood clots.

Machlus: So much more than forming blood clots. We like to think of their role in hemostasis — which is blood clot formation and keeping our vessels in shape and keeping us from bleeding out — as their day job, and they have lots of night jobs as well. They also have roles in inflammation, things like cancer and almost any kind of disease you can think of.

One of the reasons for that is because they circulate in their blood. They see all your different organs, and the proteins that are within them that get released when they’re activated are very, very diverse. So, because of that, when they become activated and release those proteins, they do it systemically.

In our lab, for instance, we’ve studied the role of platelets in lupus, obesity, kidney disease and Alzheimer’s. It’s like if you look for a role of platelets in the disease, it’s there. But really, their primary role is in helping you not die of hemorrhage.

Rath: I guess when your major role is that much of the headliner, the other stuff gets lost.

Machlus: That’s why you need them! You need them for that. But they do other things as well.

Rath: I was going to ask you what drew you into this line of work, but I can kind of hear in your voice just how fascinating this is.

Machlus: It is. I’m mostly fascinated with their mother cell, megakaryocytes, because that’s what we know the least about. We know quite a lot about platelets because they circulate in your blood, and we’ve been studying blood for a long time. But megakaryocytes are in your bone marrow, and your bone marrow is very hard to access.

So it’s really only since 1994 that we’ve been able to culture megakaryocytes. We actually have no idea, still, what stimulates megakaryocytes to begin the process of making platelets, which feels completely wild to me. And that is the question that has led me on this wild journey — the question that keeps me up at night and what I want to figure out.

And that’s the reason why we have platelet donations — because there is no drug that exists that, when you walk into a hospital that you can give someone, that would immediately trigger their body to make platelets.

Rath: Well, you’re kind of blowing my mind. I didn’t know about these cells five minutes ago that are so hugely important. I guess this is why you started your own lab, right?

Machlus: Exactly. We are doing such crazy things, like, we’re editing the genome, yet we don’t know what triggers platelet production. How could we have let this pass us by? We’re literally giving people platelets from other humans because we don’t know this fundamental answer.

We know what triggers megakaryocytes to be made — from stem cells in the blood — and we can watch them make the platelets, but we have no idea what sparks that process. And because of that, we can’t design any drugs that do it. We figured out some things that modify the process, and I think we have some hints, but it just feels so fascinating to me.

Rath: So you’ve been able to cultivate the megakaryocytes in the lab now. How much closer does that get you to getting to that understanding that you’re talking about?

Machlus: It gets us a lot closer. Culture systems, they're all models. And I think one of the things that is getting us a lot closer is making better models.

So last year, in collaboration with a lab at Oxford, we published the first bone marrow organoid, so it reproduced a bone marrow microenvironment in a well. Basically, it's so much better than just having a megakaryocyte in a dish because it's giving it the other cells it needs. So if we can better recreate the environment, I think it gives us a better chance of observing that out of the body.

We’re making better models now, so maybe we can better observe how that happens. In this bone marrow organoid, there are megakaryocytes, and there are blood vessels, and we're able to watch that megakaryocyte make platelets. So we can now start giving different conditions to see if it increases or decreases and begin back-engineering and asking the questions to get down to the molecules. That's what we need.

Rath: Before we let you go, I want to ask you about your Blood and Bone virtual seminar series. It seems like you’re enthusiastic about mentoring the next generation of scientists.

Machlus: It is what I live for. I really get my energy from sharing science with other people, and I was bereft being alone during COVID. I think it sounds trite now because so many people had seminars. I just thought of all the seminars people had prepared that would get to fair. So actually, what I did was I put up a blank Google doc with dates on it, and I advertised, “Does anyone want to give a seminar?” Because we’re all going to really miss hearing science.

This was maybe like the second day of lockdown, and I woke up the next morning and over 100 people had signed up from our community. It was this overwhelming response. I wound up hosting a seminar every day for over four months. Every day, I sat and did it, and people logged in from all over the world.

We had a Slack channel that had 700 participants. We were hosting Happy Hours. People were recruiting postdocs. It just created this beautiful, beautiful community of people that just missed science. And that just made me so happy because it created this exchange of ideas that actually maybe never would have happened.

It lasted about a year in total. But it was just one of those opportunities that came up, and I was so grateful that I was able to connect the community in that way.