Notes on Engineering Health, April 2024: Notes on Radiopharmaceuticals

The early pioneers who first used radioactive compounds in medicine died young and badly damaged—Marie Curie died of aplastic anemia in her sixties; Henri Becquerel died of a heart attack in his fifties, his skin covered in burns from radioactive emissions; Irène Joliot-Curie died from acute leukemia; and her husband, Frédéric Joliot-Curie, from liver disease. Undoubtedly, they were afflicted by their research, finding and analyzing radioactive elements, which opened up an entirely new field of study: radiopharmaceuticals and nuclear medicine. (Tragically, another of these trailblazers, Pierre Curie, survived exposure to radiation, but died young after being run over by a horse-drawn streetcar.)

Radiopharmaceutical compounds are key elements of nuclear medicine. They are a drug class containing a bioactive moiety that binds to a specific target and brings along radioactive isotopes or radionuclides. As they decay into more stable forms, these isotopes emit radiation that can be detected and measured in medical imaging or serve as cytotoxic agents when targeted at pathogenic cells such as cancer. The type of radiation emitted depends on the isotope.

– Gamma rays are used in diagnostic imaging because they can penetrate body tissues and be detected externally by cameras.

– Beta particles (electrons) and alpha particles (helium nuclei) are used in therapeutics because they deliver higher doses of radiation over short distances thereby damaging or destroying targeted cells.

Radiopharmaceuticals are designed to deliver radioactive material into the body precisely. Both the bioactive part and the linked radionuclides have evolved tremendously over time to address a range of applications and reduce toxicity concerns.


Natural Radiation
The history of radiopharmaceuticals began in the late 19th century with a serendipitous experimental finding by the physicist Henri Becquerel. Becquerel had been looking for a connection between phosphorescence and the recently discovered x-rays. In testing his (wrong it turns out) ideas, Becquerel would wrap photographic plates and objects such as a metal Maltese Cross in black paper atop which he would place uranium salt crystals before placing the bundle in the sun. When he would develop the plates, he would see outlines of the salt crystals. Becquerel concluded that the phosphorescent uranium salts absorbed sunlight and then emitted a radiation similar to x-rays.

At the end of February 1896, it was cloudy in Paris, so Becquerel stuck one of his packages in a drawer to await a sunny day. On March 1, he pulled the package out, developed the plates and much to his surprise found clear images similar to what he had found in packages exposed to sunlight. Becquerel explained the unexpected finding as spontaneous radiation from the uranium salts themselves. This discovery of natural “rays” was quickly followed by Marie and Pierre Curie’s identification of polonium and radium, discovered as they studied the properties of uranium. In 1897, Marie Curie coined the term “radioactivity.”

The potential of radioactivity to interrogate and treat disease was immediately apparent to scientists. In the 1920s and ‘30s, Georg de Hevesy used lead-212, a radioactive isotope, to investigate the absorption and movements of lead in plant systems. He ingested (!!) progressively increasing aliquots of deuterium-laced water as a tracer, showing that phosphorus was taken up and released by the skeleton, demonstrating for the first time that the bone is an active organ. The tracer concept would become central to nuclear medicine, allowing doctors to track the movement and concentration of substances within the body.

Artificial Radionuclides
Critical advancements in the understanding of nuclear physics in the 1930s and ‘40s (prompted by the war effort) accelerated the development of nuclear medicine. Most notably, the physicist Ernest O. Lawrence invented the cyclotron, a device able to accelerate charged particles to high energies, enabling the bombardment of materials leading to the production of artificial radionuclides. This invention was groundbreaking because before then researchers relied on naturally occurring radionuclides that were both hard to isolate and limited in variety. The cyclotron created a broader range of radionuclides that were essential for expanding the capabilities of nuclear medicine. Frédéric Joliot and Irène Joliot-Curie (winners of the Nobel Prize in Chemistry in 1935, the second husband and wife team to ever win the prize following Irène’s parents Pierre and Marie) used the cyclotron to bombard stable nuclides such as boron, magnesium, and aluminum with alpha particles to create new radioisotopes, contributing heavily to the development of artificial radionuclides for their use in medicine.

Their research led directly to the first therapeutic use of radionuclides in the 1940s. Based on the Curie work in artificial isotopes, Enrico Fermi synthesized an iodine isotope (I-128) and Saul Hertz used it to treat hyperthyroidism as early as 1941. He knew that iodine was quickly absorbed by the thyroid gland through normal metabolism to produce thyroid hormone, and he expected that the short half-life of the toxic isotope—around 25 minutes—would allow the gland to shrink without affecting other tissues. The remarkably successful results were the first step toward treating other thyroid diseases such as cancer.

Today
The development of new radioisotopes and labeling techniques which followed on from this first application has expanded the range of nuclear medicine in diagnostics. Technetium-99, discovered in the 1960s, became the most widely used radioisotope due to its ideal physical properties, including a short half-life and the emission of gamma rays suitable for imaging. Gamma ray-emitting isotopes detected by imaging devices such as PET (Positron Emission Tomography) and SPECT (Single Photon Emission Computed Tomography) scanners opened up the human body further and not only produced images of the internal structure of organs or tissues but also detailed their function and metabolic activities, providing valuable information for diagnosis.

Advances in physics, chemistry, and pharmacology have created more specific and effective radiopharmaceutical compounds for therapeutic use:

‍Radionuclides
Radionuclides fall into two categories, alpha and beta particles. They have different properties and are therefore suited for different types of treatment:
 – Alpha particles—like Radium-223 or Bismuth-213—consist of two protons and two neutrons, making them relatively heavy and highly charged. They have a very short range in biological tissue (typically less than 100 micrometers, a few cell diameters) and deposit a high amount of energy along their short path. Due to their high energy and limited penetration, alpha particles are extremely effective at damaging DNA and killing cells. This makes them ideal for treating small, localized tumors that require a concentrated dose of radiation without affecting surrounding healthy tissue.
– Beta particles—like Iodine-131 and Yttrium-90—are high-energy, high-speed electrons emitted by certain radioactive nuclei. They have greater penetration than alpha particles, typically traveling several millimeters to a few centimeters in tissue. The lower radiation dose over a larger volume makes them suitable for treating larger tumors and some blood disorders.

Bioactive Compounds
In the late 1980s and 1990s, scientists expanded the reach of radioactive isotopes beyond the tissues to which they were “naturally” attracted. They aimed to label their new radionuclides with vectors that bind specific targets to bring the radioactive compounds to specific cells. After a period of trial and error, they managed to tag cancer cells with a radionuclide successfully. Since then, a growing number of nuclides have been vectorized with antibodies, peptides, or small molecules to target cancer cells. When labeled and targeted with therapeutic radionuclides, peptide molecules can destroy receptor-expressing tumors, an approach referred to as peptide receptor radionuclide therapy (PRRT) which has shown success in multiple diseases, including lymphoma and prostate cancer.

The strategy of combining a cytotoxic radioactive payload and a targeting vector is similar to that of antibody-drug conjugates (ADCs). Like ADCs, the risk of toxicity and the ability to identify relevant markers in sufficient concentration made the development of these drugs challenging. However, the ever-expanding availability of more efficient and effective radionuclides—the choice of isotope, its activity level, the chemical form of the radiopharmaceutical, and the administration method — and the identification of new targets lit up the whole industry in an explosion of startups and a flurry of high-profile acquisitions. Although the excitement is palpable and warranted, manufacturing radiopharmaceutical compounds while keeping the cGMP standard regulated by the FDA has proven costly and difficult.

Radiopharmaceuticals represent a unique marriage of chemistry, physics, and medicine, offering both diagnostic and therapeutic capabilities. The Curie family’s inventiveness (and sacrifice) launched an extraordinary amount of activity harnessing the power of the atom to cure the human body.

– Jonathan Friedlander, PhD & Geoffrey W. Smith



First Five
First Five is our curated list of articles, studies, and publications for the month.

1/ The music in our genes
The age-old debate between nature and nurture is back with a surprising twist in this Current Biology paper analyzing the genetic predisposition for musical abilities of none other than Ludwig van Beethoven who composed this masterpiece among other extraordinary works. The study of the composer’s DNA from a lock of his hair revealed that he had a low polygenic score for predisposition for beat synchronization. The study is a teaching moment about how seriously one should consider these scores at an individual level and their predictive value for particular traits.

‍2/ The ageless RNA
While it was well understood that genomic DNA that resides in the nuclei of neurons can be as old as the organism itself, it was also understood that RNA was a support for information that was short-lived and quickly degraded. A European team published in Science the finding of a new species of nuclear RNA that doesn’t seem to age. The team tracked the RNA using fluorescent molecules and showed that this stable RNA was important for key cellular processes including keeping neurons alive. This discovery could open new ways to drug nucleic acids.

3/ Survival of the nicest
What if the motivating force behind our drive to thrive was cooperation rather than competition? That is the argument of a new book, Selfish Genes to Social Beings: A Cooperative History of Life by Jonathan Silvertown. Starting at the cellular level, the author makes a compelling argument that cooperation is key to multicellularity and increased complexity. He expands this idea to the organism, population, and human society levels. It is an optimistic and well-documented view of nature and human organizations for which you can find a helpful review on the Nature website.

4/ Tasting bitter herbs (throughout the body)
Humans can taste sour, sweet, bitter, umami, and salty using specialized receptors on the tongue. A recent Nature paper detailed the structure of an important protein, TAS2R14, which is part of a class of G-protein-coupled receptors that is responsible for tasting bitter foods. This particular class of bitter taste receptors turns out to be highly expressed in places outside the mouth and represents a potential drug target via allosteric modulation.

‍5/ Praise to the chemists!
In a vibrant article, Donald Weaver, a professor of Neurology, Chemistry, and Pharmaceutical Sciences at the University of Toronto, passionately pleads for recognition of chemists’ contributions to drug development. It is not doctors, physicians, or biologists who invent new drugs, but chemists. He reminisces on his career path and recounts the story of one of his patients that made him want to change his life and become a chemist. While he acknowledges the challenges of finding a treatment for Alzheimer’s disease, he is full of hope and engages a new generation of students to choose this path. As he says, “Chemists invent drugs, and drugs save lives.”



Did you Know?
In this section of our newsletter, we try to demystify common terms and structures in our work as investors.

‍LP/GP
Most venture capital funds are set up as limited partnerships, a legal entity comprising a general partner (GP) and limited partners (LPs). The GP of the venture capital fund manages the partnership and is made up of individuals employed by a VC firm.  The LPs are individual or institutional investors who supply the capital and are passive investors, as they are not involved in the fund’s day-to-day operations. This relationship between the GP and LPs is governed by a Limited Partnership Agreement (LPA) which dictates how a fund is administered. Typically, LPs will pay a management fee in addition to the carried interest that the GP receives on exited investments. The management fee and carried interest will be defined in the LPA. The GP/LP fund structure is the basis for most venture capital funds, but specifics (management fees, carried interest, hurdle rate, etc.) vary from fund to fund and are governed by the LPA.

– Haiming Chen & Dylan Henderson