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After Eureka Comes Death

As insulin prices skyrocket, diabetics turn to increasingly dangerous solutions to manage their illnesses

By Jesse Kireyev, History ‘21

Author’s Note: There’s an indescribable type of heartbreak that comes from hearing a close diabetic family member or friend tell you they cannot afford their next dose and won’t be able to for weeks. A day or two of missed insulin shots could easily end in death as it did for at least one individual mentioned in this article. It’s an especially American experience to be gripped in fear for your loved one’s life because the barebones that they need to survive is out of reach, and despite the relatively high prevalence of diabetes in the population, it’s an issue that’s starkly ignored. Mothers, fathers, siblings, and children wilting away in hospital rooms don’t grab headlines as easily as the latest political trauma, and so too often they get entirely ignored. While I chose to conclude the article on a hopeful note, it’s vital to emphasize that while we wait far too patiently for that hope to materialize, more diabetics die. Many of those who outwaited their hope will never have it again. Americans can’t wait much longer.

 

Oakland, California, has always been a hub of counterculture. Set in the heart of the Bay Area, Oakland has hosted dozens of America’s most famous hip hop musicians, visual artists, social justice advocates, and tech pioneers. This cultural backdrop has facilitated the creation of the Open Insulin Project: a communal space where diabetics and biohackers meet twice a week to try to create an open source guide that would let type 1 diabetics produce insulin at home. 

Diagnosis of this condition was once a death sentence. Prior to the discovery of artificially produced insulin, a child diagnosed with type 1 diabetes had only about a year or two to live after diagnosis [1]. Type 1 diabetes is an autoimmune disease that develops when the immune system starts treating beta cells in the pancreas as a threat and attacks them. The beta cells are responsible for insulin production, so as they are attacked, the pancreas becomes unable to produce insulin. The reasons for why this happens are unknown — current theories suggest environmental and hereditary factors may play a big role, but lifestyle factors do not seem to affect it significantly. This differs from type 2 diabetes, which causes your body to resist the effects of insulin rather than making it unable to produce it [2]. Insulin is a hormone that your body naturally produces to regulate the amount of glucose, or blood sugar, in your system. As type 1 diabetes develops and insulin production stops altogether, the body loses its ability to regulate blood sugar unless insulin is supplemented through injection. 

The grim sites of hospital wards full of dying children pushed three scientists at the University of Toronto—Sir Frederick Banting, Charles Best, and JJR Macleod—to discover insulin in 1921. The theory of injecting insulin to regulate blood sugar wasn’t developed until a year later by James Collip, but the first patients treated with insulin injections suffered from severe allergic reactions due to the insulin’s impurity. Collip discovered a way to purify it, putting insulin to use to save children dying from diabetic ketoacidosis—a dangerous diabetic complication that can often end in a coma or death that develops when the body, lacking glucose, begins to produce ketones that acidify the blood. Shortly after discovering and producing insulin, the researchers refused any compensation for their discovery and gave exclusive production rights to a chemical manufacturing firm in Indianapolis, which was to sell insulin at three cents per  unit. As a New York Herald article from 1923 put it, Sir Frederick Banting set out to make insulin “available for even the poorest sufferers from diabetes” [3]. Despite Banting’s intentions, the price of insulin has since soared.

The current cost to produce a single vial of human insulin is somewhere in the range of two-and-a-half to three-and-a-half dollars, and a year’s supply of the medicine could be sold to type 1 diabetes patients for as little as seventy-two dollars, a cost that is not only affordable to consumers but still produces a large profit margin for the pharmaceutical companies creating it [4]. And yet insulin prices remain far higher than they theoretically should be. A survey of medical prices conducted by the Health Care Cost Institute showed that in 2016 type 1 diabetics paid an average of $5,705 for insulin, over seventy-nine times the cost of what medical researchers believe they should be paying [5]. American diabetes patients paid an average of $300 for a vial of Humalog, a specific type of insulin, in 2019. That same vial costs just thirty-two dollars  in Canada [6]. As a result, more people are trying to fight back against these skyrocketing costs. 

Drug development can drain millions of dollars from a pharmaceutical company’s budget, meaning companies have to sell their drugs at high prices to recoup the costs of development. New developments to certain medications can temporarily raise their prices, which is a reason often used by pharmaceutical companies to defend their price increases, but that’s not the case with insulin. Dr. Nicholas Argento said in an interview with Business Insider, “The products that are out are not really new. They may have tweaked the manufacturing process and[…]they have better delivery pens and the like, but the increase in price has been astronomical” [7].

While the base drug itself hasn’t seen significant development in decades, the patent on it still remains, and keeps getting extended. “Drugs are kept on patent by making somewhat fairly small fluctuations or modifications to the particular thing, like insulin,” said Dr. Huising. This effectively prevents the production of a cheaper, generic version of the drug, leaving diabetics to rely on insulin produced by only three suppliers in the United States. Canadian patients are able to buy insulin at lower costs due to increased market price regulation, as well as the fact that Canada allows generic insulin into the market, side-stepping the patent issues that generic insulin would face in the United States. And the patents still have a while to go before expiring: just last year, French pharmaceutical company Sanofi, one of the three insulin suppliers in the United States, got its patent extended to 2031. The medical advocacy non-profit, Initiative for Medicine, Access, and Knowledge, points to this as one of the main culprits behind the price increases, stating in its 2018 report, “The U.S. cannot fix the drug pricing crisis until it solves the drug patent problem” [8]. 

When comparing the price of insulin produced by each of these three companies, it is clear that each company sells its product at almost the exact same price, and price increases between the three companies have remained almost identical over the past few decades. While the companies deny any collusion or price fixing, by law, pharmaceutical corporations are not required to provide the reasons behind price increases, and they can raise them without limit [9]. The issue has become so dire that in 2018, the Congressional Diabetes Caucus released a report stating that the current system is “unfairly putting insulin out of reach, placing millions of lives at risk” [10].

Placing millions of lives at risk is not an over exaggeration: without enough insulin, blood sugar rapidly increases. A diabetic with high blood sugar runs the immediate risk of developing diabetic ketoacidosis, alongside long-term cardiovascular and nervous system problems, which can significantly shorten lifespans. According to Dr. Kasia Lipska, an assistant professor at the Yale School of Medicine, “About 1 in 5 people with type 2 need insulin to prevent short-term and long-term complications like blindness, kidney failure, and dialysis and heart disease” [11]. For other types of non-gestational diabetes, the risk is more immediate: “Insulin is a life-saving drug, people need it,” says Dr. Huising. “If you have type 1 diabetes and no insulin, you die.”

These problems can emerge from missing just a few doses of insulin, something that many diabetics increasingly have to resort to due to its cost. Lipska et al. published a study in the journal JAMA Internal Medicine that found that over a fourth of diabetes patients have had to cut back on insulin dosage due to the high price of the medicine. The human costs of insulin prices are very real. In a CBS interview, the mother of a man who died because he couldn’t afford his medicine spoke out against the costs. Alec, a young man with diabetes, began to ration his insulin when faced with a $1,300 price tag. Unfortunately, after struggling under a diabetic coma, the lack of insulin cost him his life. “I wanted to be there with him, to hold his hand, or to call for help. And then I think about if he had never moved out, if he had lived at home, somebody would have seen the signs,” she said. “I’ll probably feel guilty every day for the rest of my life” [12].

It is within this context that a number of rogue diabetics in Oakland have begun to try to synthesize their own insulin supply. The Open Insulin Project was started in 2015 by Anthony Di Franco, a type 1 diabetic who struggled for years with being able to buy his insulin. The project utilizes biohacking—a movement that applies do-it-yourself, rule-averse hacker practices to the exploitation of genetic material—to create a homebrew form of insulin for type 1 diabetics. The project’s motives are exceptionally ambitious, given that almost none of the people involved are trained biochemists. Di Franco and other project leaders such as David Anderson lack experience in biological or chemical sciences, and neither work in relevant fields—Di Franco is a computer scientist, and David Anderson is pursuing a degree in business economics [13]. The Project aims to one day create a fully safe and functional form of insulin, and recent developments in the chemical process have shown some promise. Currently, the Project is hoping to convert proinsulin—insulins’ chemical precursor—to full insulin, after which they will attempt to scale their process up [14]. But some have their doubts. Hank Greely, a professor at the Center for Law and Biosciences at Stanford University, warns that “manufacturing pharmaceuticals is difficult, painstaking, and dangerous. If you get the dosing or the strength on the insulin wrong, it’s death. If you let contaminants into the insulin, it’s possible death. If your insulin breaks down too quickly in storage, it’s death” [13].

Dosing is a difficult challenge in a homebrew environment, where biohackers might not be able to access the proper equipment to create safe and stable insulin with consistent doses and without contaminants. Immunogenic reactions—wherein a foreign molecule entering the body provokes an immune system response—predominates the list of concerns over impurities. “You’re injecting something. If there is an impurity there that is a foreign molecule, then your immune system might start to respond,” Dr. Huising said. “Doing it at scale with a quality that is consistent is extremely challenging to do. It’s not that hard to make it if you’re a trained biochemist, but making it with a quality and consistency that is compatible with injecting it as a drug over multiple batches is hard to achieve.”  Nor does the Project have access to most of the biochemistry equipment Dr. Huising insists is necessary to create insulin safe for injection. “The motivation behind wanting to make insulin is clear,” he said. “But doing it homebrew style is just dangerous and irresponsible.” 

Due to this, the Open Insulin Project may face legal challenges from the FDA and other regulatory agencies, challenges that the Project may not have the money or resources to address.  This is not a problem that has escaped the minds of those running the Project, as they currently are trying to figure out the legal issues surrounding human testing and safety of human consumption. That is why the project has been focusing on creating a do-it-yourself guide to synthesizing insulin at home—while the FDA can regulate distribution of medicine; the first amendment stops them from regulating the distribution of a guide on how to make the medicine. 

But the situation may soon change enough that the need for the Open Insulin Project will fade away entirely. Over the past few years, the FDA has been pursuing paths to change insulin regulatory procedures, introduce generic insulin to the market, and lower the costs of the drug—policies that the last three presidential administrations have publicly advocated for. Dr. Huising has hope that this public pressure might help insulin prices fall within the next few years—“Even in the past couple of years, there has been talk in Washington about how big pharma does overcharge. I don’t think that’s necessarily a left or a right talking point,” he said. “There is a recipe there for improvement, where we demand that insulin is made available at prices that don’t force people to self censor or self limit how much insulin they dose themselves with.” 

 

References

  1. Editor. Diabetes history. Diabetes.co.uk. 2019 Jan 15. https://www.diabetes.co.uk/diabetes-history.html
  2. Causes of type 1 diabetes – JDRF. Jdrf.org. 2017 Oct 17. https://www.jdrf.org/t1d-resources/about/causes/
  3. Moulton Weekly Tribune. Newspaperarchive.com. https://moultonpl.newspaperarchive.com/moulton-weekly-tribune/1923-12-07/page-8/
  4. Gotham D, Barber MJ, Hill A. Production costs and potential prices for biosimilars of human insulin and insulin analogues. BMJ global health. 2018;3(5):e000850.
  5. U.S. insulin costs per patient nearly doubled from 2012 to 2016: study. Reuters. 2019 Jan 22. https://www.reuters.com/article/us-usa-healthcare-diabetes-cost-idUSKCN1PG136
  6. Goldman B. The soaring cost of insulin. CBC News. 2019 Jan 28. https://www.cbc.ca/radio/whitecoat/blog/the-soaring-cost-of-insulin-1.4995290
  7. Business Insider. Why insulin is so expensive. 2019 Feb 12. https://www.youtube.com/watch?v=7Ycd8zEdoVk
  8. I-mak.org. 2018. https://www.i-mak.org/wp-content/uploads/2018/08/I-MAK-Overpatented-Overpriced-Report.pdf
  9. Thomas K. Drug makers accused of fixing prices on insulin. The New York times. 2017 Jan 30. https://www.nytimes.com/2017/01/30/health/drugmakers-lawsuit-insulin-drugs.html
  10. Skyrocketing insulin cost: Congressional Diabetes Caucus highlights need and ways to bring prices down. House.gov. 2018 Nov 1. https://diabetescaucus-degette.house.gov/media-center/press-releases/skyrocketing-insulin-cost-congressional-diabetes-caucus-highlights-need
  11. Adam.com. http://pennstatehershey.adam.com/content.aspx?productId=35&gid=4470
  12. CBS This Morning. Mother says son died “because he could not afford his insulin.” 2019 Jan 4. https://www.youtube.com/watch?v=Zp_1ohad0Tg
  13. Osterath B. Deutsche Welle (www. dw.com). 2019. Do-it-yourself insulin: Biohackers aim to counteract skyrocketing prices. https://www.dw.com/en/do-it-yourself-insulin-biohackers-aim-to-counteract-skyrocketing-prices/a-48861257
  14. Di Franco A. New frontiers for the New Year. Openinsulin.org. 2018 Dec 31. https://openinsulin.org/our-blog/new/

Finding a Solution in the Source: Exploring the Potential for Early Beta Cell Proliferation to Disrupt Autoreactive Tendencies in a Type 1 Diabetes Model

By Reshma Kolala, Biochemistry & Molecular Biology ‘22

Residing in the pancreas are clusters of specialized cells, namely alpha, beta (), and delta cells. cells, more specifically, are insulin-secreting cells that are instrumental in the body’s glucose regulation mechanism. An elevation of the extracellular glucose concentrations allows glucose to enter cells via GLUT2 transporters, where it is subsequently metabolized. The resultant increase in ATP catalyzes the opening of voltage-gated Ca2+ channels, triggering the depolarization of the plasma membrane which in turn stimulates insulin release by cells (1). In individuals with Type 1 Diabetes (T1D), however, pancreatic islet beta cells are damaged by pro-inflammatory cytokines that are released by the body’s own immune cells. The loss of functional beta cell mass induces a dangerous dysregulation of glucose levels, resulting in hyperglycemia along with other harmful side effects. The absence of a regulatory factor in the bloodstream forces those with T1D to take insulin intravenously to remedy the consequences.  

A new study led by Dr. Ercument Dirice, a Harvard Medical School (HMS) instructor and research associate at the Joslin Diabetes Center. has suggested that an increase in cell mass early in life diminishes the autoreactive behavior of immune cells towards cells, therefore halting the development of T1D (2). In a typical T1D model, the secretion of antigens from cells induces a response from the body’s immune cells. These immune cells bind to the epitopes (the recognizable portion of an antigen) that are displayed on the surface of professional antigen presenting cells (APC’s) which are littered throughout the pancreatic islets (3). This binding action induces a destructive autoimmune response to antigens secreted by cells, resulting in loss of functional beta-cell mass. It was found however that by increasing cell mass at an early age where the organs of the immune system are still developing, the immune cells stopped attacking cells. 

The novel approach presented by Dirice et al. departs from the traditional method of targeting various other components involved in the destructive autoimmune response, namely APC’s or the pro-inflammatory cytokines associated with T1D progression. This method instead focuses on the source of the autoimmune marked “pathogenic” antigens, the cells themselves. 

The studies were completed using two models of female non-obese diabetic (NOD) mice. One was a genetically engineered model of female mice (NOD-LIRKO) that showed increased cell growth soon after birth while the second model was done using a live mouse that was injected at an early age with an agent known to increase cell proliferation. While maintaining more than 99.5% isogenicity (4), it was found that the mice with increased cell mass had a significantly lower predisposition to develop diabetes when compared against the NOD control mice, which developed severe diabetes between 20-35 weeks of age. The study also observed the interaction between the modified cells and immune cells by monitoring the concentration of these immune cells in the spleen. In doing this, researchers were able to conclude which mice had a greater risk of developing T1D based on if mice had an abnormal increase in the concentration of these cells. 

At first glance, this method appears counterintuitive as an increase in cell mass may lead one to naively assume that this would result in increased autoantigen production. This precise hypothesis illustrates the beauty of this approach. Although the specific details of this mechanism have yet to be made clear, it is believed that the rapid turnover of cells “confuses” the autoimmune reaction. The proliferated   cells present unusual autoantibodies that are not observed in typical T1D progression. Dr. Rohit Kulkarni, a fellow HMS professor and researcher at Joslin noted that there is thought to be some alteration in the new cells where the autoantigens typically produced are reduced or dilated (2). As a result of the slow presentation of antigens, there is a lower proportion of autoreactive immune cells. This essentially results in a “reshapen immune profile that specifically protects   cells from being targeted.” Some degree of autoimmunity would continue to exist in the body, so further immunosuppressive treatment would be required. 

Early cell proliferation has been previously speculated to have a protective effect in those with reduced functional cell mass as in a Type 1 Diabetes model. Once this preventative quality is better understood, applications of this research may be further explored. Despite still being in the beginning stages, this novel approach holds tremendous potential for application to T1D if this method is able to be translated to a human model. The massive prevalence of a T1D diagnosis is illustrated by 2014 census data that states that T1D affects roughly 4.7% of the world’s adult population. Although extensive research continues to be done on several aspects of the disease, the introduction of new data by Dirice et al. may push us a small step closer to solving one of the body’s greatest metabolic mysteries. 

References

  1. Komatsu, M., Takei, M., Ishii, H., & Sato, Y. (2013, November 27). Glucose-stimulated insulin secretion: A newer perspective. Retrieved from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4020243/
  2. Yoon, J., & Jun, H. (2005). Autoimmune destruction of pancreatic beta cells. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/16280652
  3. Pushing early beta-cell proliferation can halt autoimmune attack in type 1 diabetes model. (2019, May 06). Retrieved from https://www.sciencedaily.com/releases/2019/05/190506124102.htm
  4. Burrack, A. L., Martinov, T., & Fife, B. T. (2017, December 05). T Cell-Mediated Beta Cell Destruction: Autoimmunity and Alloimmunity in the Context of Type 1 Diabetes. Retrieved from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5723426/
  5. Dirice, E., Kahraman, S., Jesus, D. F., Ouaamari, A. E., Basile, G., Baker, R. L., . . . Kulkarni, R. N. (2019, May 06). Increased β-cell proliferation before immune cell invasion prevents progression of type 1 diabetes. Retrieved from https://www.nature.com/articles/s42255-019-0061-8?_ga=2.76180373.1669397493.1557550910-1092251988.1557550910

Prenatal Exposures and Risk for Chronic Diseases Later in Life

By Marisa Sanchez, Genetics ’15

Most people know that poor diet, lack of exercise, and smoking as an adult can increase the risk of developing cardiovascular disease (CVD) and Type II diabetes. However, research over the past couple of decades has shown that risk for CVD and type II diabetes could begin as early as prenatally through adverse exposures, such as overnutrition and placental insufficiency. Some mechanisms involved in determining risk for CVD and Type II diabetes are oxidative stress, inflammation, lipotoxicity, and epigenetics. (more…)