Author: Mareena Hyypiä

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From the Hub of Thousand Lakes to the World’s Leading Biotech Hub

“Everything is bigger there, one needs a car to get anywhere, the baseball and football they play are something else, and it is supposedly the college town and biotechnology hub.” This was the rather stereotypical view of Boston I had seen and heard from multiple sources (such as many American movies) before crossing the Atlantic for the first time and landing to one of the oldest cities in the United States. For the next six months, I was going to work as a HiLIFE Visiting Graduate Researcher at the Wyss Institute for Biologically Inspired Engineering at Harvard University.

The Wyss Institute has a strong emphasis on translating bioinspired innovations and research findings into clinical use. The number of patents, licenses and start-ups deriving from the Wyss is astonishing: during the 14 years of the institute’s existence, over 4000 patents have been filed and 56 start-ups founded. To enable this technology translation, Wyss operates through extensive collaboration with industry, government, foundations, and philanthropists. The Wyss teams have experts from different fields ranging from engineering to veterinary medicine, from general medicine to bioinformatics, and from molecular biology to bioethics.

The original six months got extended and therefore, during the past eight months, I got the opportunity to work in Donald Ingber’s (M.D., Ph.D.) lab in the Brain Targeting Program at the Wyss. Of these months, six I was present in Boston and the final two contributing to the program remotely from Finland. The Brain Targeting Program aims at discovering and developing new brain transport shuttles and brain-targeted therapies to more efficiently treat diseases in the central nervous system, such as neurodegenerative diseases and brain tumors. For reading more about the research topic, please have a look at my first blog post. The internship was certainly the most remarkable experience during my Translational Medicine Master’s studies at the University of Helsinki, and I could have not imagined a better way to complete my studies.

Laboratory setting
My dear lab bench at the Wyss Institute

What comes to my presumptions about Boston, at least one of them proved very accurate. According to the EPM Scientific (2023), this year, Massachusetts has earned the title of “the largest and leading Biotech hub in the world”. The life science and biopharmaceutical sector has grown massively in the Boston metropolitan area, this growth corresponding to increase in venture capital, employment rate, and governmental funding received. In fact, there are almost 1000 biotech companies, and over 60 colleges and universities in the area! Combine this with specialized medical centers and university teaching hospitals such as Dana-Farber Cancer Institute, Boston Children’s Hospital, Beth Israel Deaconess Medical Center, or Massachusetts General Hospital, and you have the foundation for boundless opportunities.

During my daily bike commute along the Charles River, not only could I enjoy the views of prestigious red brick buildings from the 18th century, but also appreciate the modern glass office buildings with biopharma company names like Biogen, Takeda, Pfizer, or Eli Lilly written on top of them. The different universities, non-profit organizations, venture capital firms and other groups were organizing various incubator and accelerator programs with pitching events open to attend for anyone interested. In addition, there were free of charge conferences, seminars, and lectures given by top scholars of the field, by people you had previously only seen in Ted Talks or had read their state-of-the-art work from Nature, Cell, and Science. You would see advertisements of novel RNA technology in the subway and randomly hear discussion of a given research topic in almost any bar or restaurant in the city. Even if you would go on a walk in a national park hundreds of miles outside Massachusetts, you would encounter other hikers with their company or institute swag, portraying very clearly the amount of biotech and medicine professionals in Boston and Massachusetts area.

Building with pillars and a yard surrounded by trees
The Quad at Harvard Medical School

For the work of our Brain Targeting Program and my internship this meant that I would be immersed into science, innovation, and biotechnology. Truly feeling like a child in a candy store. It was deeply inspirational and improved my thinking to be more creative yet critical. I could meet like-minded people and create networks with scientists working on topics of my interest. We could also work with clinicians and hospitals from around the corner and foster collaborations with other research groups somewhat effortlessly.

To conclude, I wanted to summarize three main learnings from my internship experience that are not only applicable to Boston but can be utilized in other contexts as well.

1. Keep an open mind

The amount of biotech companies and research initiatives makes it possible for anyone to find their research niche from Boston. There are hundreds and hundreds of job posts on LinkedIn, in positions rarely – if at all – seen back home in Finland. The challenge is not how to find what you would like to do, but how to choose from all the possibilities. That is why especially if you are in your early career, keep your mind, eyes, and options open.

Participate in different events, listen to talks from various specialties from academia and industry, talk to undergrads, PhDs, professors, R&D scientists, COOs, patient representatives… and you never know if you happen to sit next to a company CEO ready to hire a talent. Reflect on what you already know and have experience on, what would you like to learn, what is your aspiration, and get inspired. If you cannot travel to a big biotech center at this moment, see possibilities online or gather information and plan possibilities for a research visit, for example via funded traineeships or short training courses.

2. Networking is key

Sorry, I know you have heard this a million times, but it just is so important… All the opportunities and events you attend will also gather important and interesting people for you to meet. These people can provide you with valuable insights into your research and career or introduce you to other connections. So even if you would not necessarily consider yourself the most outgoing person and have always felt that networking is anxiety provoking and definitely not for you, dare to get in contact with and meet people.

In addition to introducing yourself and engaging into conversations spontaneously in events, you can send emails and meet people in person after you have had some time to think what you would discuss with them. It is not a bad idea either to review the speakers of an event beforehand and formulate questions you would like to ask them. In this way you will feel more confident and importantly, not waste anyone’s time. Even though the art of small talk is very much mastered in the United States, and it is a big part of the culture, people are busy and appreciate using their time well. Yet, avoid thinking of what you have to say is not of importance and because of it cause you not to talk to people. Despite their overbooked schedules, it was amazing to see how top scholars with over 100 000 citations would stop and truly listen to what you had to say, no matter in which career stage you were.

But in all, you will get the most out of these situations when you are clear and concise. Thus, tell honestly who you are, what you would like to do and learn, and ask for advice or even collaboration if you have a potential idea. You can also create a short pitch for yourself, it will help you to focus. And remember to be gentle with yourself, practice makes perfect.

People in an auditorium
Brain Targeting Program Consortium Meeting. Picture courtesy of the Wyss Institute at Harvard University

3. Have fun and explore outside the hub

Even though Boston, or any place you work and study, is such an exciting place considering your career, do not just biotech and network 24/7 – even if conversations with your friends would every now and then slip to the lab experiments and recently approved therapeutics. It is good to take some distance from constantly thinking about career and go explore the city and its surroundings. Go to the nature, delve deep into the history, visit art museums, join block parties, and enjoy the culinary scene. This will give you a full internship experience which should not be just fun science but fun experiences overall!

The HiLIFE Research Trainee Scholarship gives you a unique possibility to work and contribute to science nearly anywhere in the world and with a vast amount of life science topics. The opportunities for you to go after your dreams are out there. What will be your path?

 

Reference

EPM Scientific. (2023). Boston is Now the Largest Biotech Hub in the World. https://www.epmscientific.com/blog/2023/02/boston-is-now-the-largest-biotech-hub.

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Granting a Drug an ID Badge – Harnessing Receptor-Mediated Transcytosis for Crossing the Blood Brain Barrier

Imagine an agency headquarters with tight security policies in place. There are security guards on all doors and no entry without an ID badge. Various employees pass by the gate, all with different job titles and responsibilities. Entrance is also granted for the supportive personnel such as maintenance, cleaning services, and catering. Everybody knows their own specialized role and together with a strong management it is made sure that everything flows in a highly organized manner. Occasionally, an intruder tries to invade the establishment, but they are swiftly stopped by the security and police officers who arrive just a moment later to make sure nothing was stolen, and no one harmed. And if something or someone was to be injured, a team of healthcare professionals would arrive to take care of the situation.

In a similar way, in our bodies, molecules are travelling in the bloodstream and when wishing to enter the brain they arrive to the gate of the blood-brain barrier, or shorter the BBB. During my HiLIFE Research Trainee internship, I got an opportunity to join the Brain Targeting Program at the Wyss Institute for Biologically Inspired Engineering at Harvard University. Research in this translational program centers around the study of the BBB.

What is the Blood-Brain Barrier?

The BBB is a highly specialized structure consisting of endothelial cells that form the blood vessel wall or lumen. These cells are located very close to one another as they form the so-called tight and adherens junctions by binding to multiple proteins. This compact structure allows a limited number of molecules to pass through the BBB. Molecules can pass through via diffusion only if they are small enough or lipid soluble. Another mechanism to cross the BBB is by utilizing transport molecules which carry some substances from the blood to the brain parenchyma (that is, the functional tissue of the brain). Thus, only if the molecule has a correct ID badge, it can enter to the brain.

In the BBB, on the brain side, endothelial cells are enclosed by other cell types: pericytes and the end-feet of astrocytes that support the integrity of the barrier – similar to those security guards in the agency headquarters. To protect the brain from the occasional invasion of intruders, there are microglial cells which work with astrocytes to engulf unwanted molecules or injured cells, and produce cytokines which amplify inflammatory signals to increase the body’s response to the intruder. There is also an efflux mechanism that can expel the uninvited guests who manage to slip through the BBB. Not only do astrocytes contribute to the integrity of the BBB, but they also connect neurons to the vasculature. Thus, there is dynamic communication between the blood vessels and the brain to keep the entire structure highly functional – in our agency example they function like a network of guards with their security earpieces.

Together, the BBB with all the different cell types form the neurovascular unit. This specialized structure is distinct from any other blood vessels in the body, and it therefore also functions very uniquely. It maintains the regulation of blood, oxygen and nutrient flow, immune response, and waste clearance which are all crucial for the homeostasis – the self-regulated normal functioning – of the brain and the body.

Image representing blood vessel surrounded by pericyte and astrocyte cells. On the brain parenchyma side neurons and microglia.
Schematic view of the blood-brain barrier. Created with BioRender.com.

The Challenge for Delivery of Therapeutics into the Brain

As much as the BBB protects the brain from unwanted guests such as microbes and toxins, it also very effectively inhibits various drug molecules from reaching the brain. The entry of up to 98% of small-molecule drugs and 100% of larger macromolecular therapeutics is blocked by the BBB. This makes it difficult to treat different diseases affecting the central nervous system, such as neurodevelopmental and neurodegenerative diseases or brain tumors.

Various methods for enhancing brain drug delivery have been developed over decades, yet only a few have proven effective. Some of these technologies need surgery or other invasive methods such as deep brain stimulation, while others such as receptor-mediated, nanoparticle carrier, or focused ultrasound strategies are non-invasive. Our Brain Targeting Team at the Wyss Institute focuses on target discovery and validation utilizing the non-invasive receptor-mediated method, named as receptor-mediated transcytosis, for more efficient brain drug delivery. My main tasks involve handling human brain tissue samples and analyzing both transcriptomic and proteomic data to identify and assess the transport potential of numerous targets.

Receptor-mediated transporters are endogenous proteins located at the BBB blood vessel wall that can have various functions in the body. For example, the most studied receptor-mediated transporter, the transferrin receptor, normally functions in iron uptake from the cell membrane inside the cell. Antibodies can be engineered to bind to these receptors in a way that also other molecules than only the endogenous ones can be internalized. Antibodies linked with desirable therapeutics and designed to utilize these transporter targets are often referred to as Trojan horses, as they are only allowed to cross the BBB when in disguise, subsequently exerting their therapeutic effects once inside the brain. Thus, transferrin receptors can recognize an antibody while inadvertently allowing the entire complex to be carried in the brain without the body’s surveillance system recognizing the foreign drug molecule.

Blood vessel on the bottom on the image, lined by endothelial cells. On top pericytes that are enclosed by astrocyte end-feet. Drug from the blood vessel is carried across the blood-brain barrier with a receptor protein.
Schematic view of the receptor-mediated transcytosis for drug delivery across the blood-brain barrier. Created with BioRender.com.

I prefer to imagine that the BBB and therapeutic compounds are on the same side of the battle. Thus, instead of a Trojan horse, this technology harnesses the capabilities of our body so that the BBB offers a helping hand in drug delivery and welcomes an additional aid to battle against protein aggregates found from neurodegenerative diseases or tumor cells in brain cancers when our body and its cells need assistance. Ultimately, it is about granting an ID badge for the drug, for the invited guest in the headquarters of our wondrous body.

A little bit about me:

I am a Master’s student in Translational Medicine at University of Helsinki, currently located in Boston, United States, to conduct a six-month-long internship at the Wyss Institute at Harvard University. In my M.Sc. studies I specialize in translational neuroscience and personalized medicine. My Master’s thesis looked into the molecular mechanisms behind Alzheimer’s disease and while in the midst of my experiments, I got enchanted about the BBB. Therefore, I am deeply thankful and excited to contribute to the Brain Targeting Program at the Wyss where innovations are translated into clinical practice. My next HiLIFE Trainee blog post will provide more insights into my internship experiences, so stay engaged for more!

Mareena Hyypiä