Category Archives: Science

How Biogen’s Alzheimer’s Drug impacts our wallets, and sets a very dangerous Precedent

This was first published as an op-ed in the Buck’s County Courier Times, February 9, 2022.

I am a scientist and have worked in the pharmaceutical industry. I believe in and love science.

I am also a retired senior citizen, dependent on Social Security and Medicare. Hence, costs are important to me, especially that of medicines. Biogen’s antibody aducanumab — marketed as the brand name Aduhelm — for Alzheimer’s disease should not have been approved in the first place.   

The approval process was torturous. Two large trials showed no convincing clinical benefit, that is, slowing patient’s cognitive decline. An independent advisory committee voted overwhelmingly against approval. Yet it was approved.   

This raises some unpleasant questions. Why was it approved and who benefits? Not the patients. A famous line comes to mind, “Just follow the money.” There is a reason why people are increasingly skeptical about the U.S. Food and Drug Administration, FDA; the Centers for Disease Control and Prevention, CDC; and what doctors say.  

It was initially priced at $56,000 per annum, a totally outrageous price. It was later cut back to $28,200 which is interesting in itself. If Biogen can make a profit on this price, how or why did they initially charge $56,000? To fleece patients because they could? Obviously, Biogen is still making a tidy profit at the lower price.  

The Medicare Part B premium was increased by $22 this year, of which $11 will be used to create a fund to pay for this drug. This is the first time one pricey drug has led to a premium increase for all Medicare recipients, not just affected patients.   

Why? Because Aduhelm is given as an intravenous infusion in the doctor’s office. This has to stop or every pharmaceutical company that develops antibodies as drugs — there are many and it’s increasing — will be tempted to take this route.   

I can almost visualize the ads on television. A well-dressed and well-groomed elderly person intoning in a rich baritone, “I can feel my memory improving after I started taking this. It makes me feel sharper and younger. It could do the same for you. Talk to your doctor.”  

Very seductive indeed. Naturally, seeing these ads, seniors will rush to their doctors to clamor for it. And that, precisely, is the goal. Biogen makes a lot of money. Benefit for the patients? Very questionable.  

And Medicare part B premiums will keep spiraling upward, $22 this year, then $50, maybe $150 the year after. Can retirees on a fixed income afford this increase, especially with inflation running rampant? And can Medicare keep up without raising taxes and/or cutting benefits?   

The recent Center for Medicare and Medicaid Services, CMS, decision is to pay only for CMS approved clinical trials with Aduhelm until its efficacy is clearly established is therefore necessary. This plan is nicely explained in Bach and Garthwaite’s (June 17) opinion piece.   

Health care costs are bankrupting us. I am constantly amazed at the exhortations from our elected representatives to do something about it and then their inability to follow through. Maybe they cannot or probably will not.  

But we can do a few things. First, start by writing or calling our elected representatives about this problem. They know but they need to hear our frustration. There needs to be political action. And second, try and maintain a healthy life style through diet and exercise. This will lead to fewer doctor visits and fewer medicines to take. We will benefit on many fronts. Save money and enjoy a better quality of life.   

The Elegant Simplicity of Nature: The Fibroblast Growth Factor (FGF) Family.

Picture above depicts spiral forms found in developing systems throughout the universe. Left, the Pinwheel Galaxy 25 million light years from earth. Photo, the Hubble Consortium, NASA, ESA. Right, a conch shell on my table here on earth. Photo, Ranjan Mukherjee

Nature is elegant in its simplicity. There are a set of laws that explain her workings. They are simple, elegant and sometimes, used repeatedly. Consider the gravitational force between two bodies, first propounded by Newton. It is a force that varies inversely as the square of the distance (the inverse square law). Gravitation is a universal law, not because we have tested it everywhere in the universe (an impossibility) but because we have not seen any deviation anywhere yet. In fact, the trajectories of our spaceships and space probes are calculated largely based on these equations and they have held up so far with the space probe Voyager exploring right up to the cold wastes at the edge of our solar system. The inverse square law also explains another attractive force, the electrostatic force of attraction between two opposite, stationary charges (Coulomb’s law). These laws have withstood the test of time.

The same is true with life and its evolution. A useful paradigm like the genetic code is used throughout the animal kingdom. The four nucleotides that form a DNA molecule, the twenty amino acids that give rise to proteins are found in all bacteria, plants and animals. Evolution has selected for these and eliminated countless others. The eliminated ones are lost to history unless something turns up in the fossil record. When something so uniquely perfect is found, it makes sense to keep reusing the basic framework with subtle modifications to satisfy the specific needs. One example is the spiral forms seen in certain developing systems, inanimate or living, as gigantic and far flung as a faraway galaxy or as simple and down-to-earth as a growing sea shell (figure above). A second example, the main subject of this article, is The Fibroblast Growth Factor (FGF) family.

Consider how a multicellular organism grows from a single, fertilized egg. The single egg divides into two, then four, eight and so on. Soon the cells in the developing embryo begin to get organized into a particular pattern that heralds the shape of the adult to come. Regions like the limb bud begin to grow and then, after a fixed interval, stop growing. There must be signaling cues that instruct these cells where to grow, when to grow and when to stop. These cues are the growth factors. Fibroblast Growth Factors (FGFs) belong to this family of signaling proteins. They are extracellular signaling molecules that mediate a whole host of cellular processes; growth, proliferation, differentiation, angiogenesis, organogenesis, cell survival, epithelial repair and wound healing.

The first members, FGF1 and FGF2 were identified in the early 1970s. They induced proliferation of fibroblasts, hence the name: Fibroblast Growth Factors. At that time, they were called acidic FGF (aFGF) and basic FGF (bFGF) respectively, based on their isoelectric point. Unfortunately, the FGF name has stuck even though later members do not cause cell proliferation. Since then, 22 members of the mammalian FGF family have been identified based on sequence homology. They can be further sub-grouped according to their mode of action. Most of them act locally, either in a paracrine or autocrine manner. Notable examples of this subfamily are FGF1, FGF2, FGF7 and FGF10, to mention a few. These FGFs utilize heparin sulfate proteoglycans found on the cell surface and extracellular matrix as essential cofactors.

In contrast, three of the family members, FGF19, FGF21 and FGF23 are secreted directly into the bloodstream and act at distal sites in an endocrine manner. These do not utilize heparin sulfate but do require alpha or beta-klotho as essential cofactors. Recent studies including crystal structure analysis indicate these cofactors are essential to their mechanism of action.

The last group of FGFs (FGF11-FGF13), are not secreted and act intracellularly by modulating voltage gated ion channels.

The autocrine and endocrine FGFs mediate their activity by binding to and activating four FGF receptors (FGFR1 – FGFR4). These belong to another large family of transmembrane receptors, the receptor tyrosine kinases. Upon binding of the FGF ligand to the extracellular domain, there is a structural reorganization of the receptor dimer which induces phosphorylation at specific tyrosine residues in the intracellular domains. These, in turn, activate a number of signaling pathways depending on the ligand and cell type that lead to the dizzying list of activities mediated by the FGFs.

Perhaps, way back in time, such a signaling molecule and its cognate receptor evolved in a prehistoric life form. It proved versatile and useful. Nature is efficient. It reused the paradigm for other related purposes. The relevant genes were duplicated, random mutations were selected for by the inexorable forces of natural selection and soon several growth factors and kinase receptors appeared controlling the many different processes needed to grow and sustain a multi-cellular organism. Some examples are the Epidermal Growth Factors, Insulin and Insulin like Growth Factors, Vascular Endothelial Growth Factors and the Fibroblast Growth factors. The FGFs are the largest of this family with 22 members.

Recombinant FGF2 is used for the topical treatment of burns, skin grafts, recalcitrant skin ulcers, diabetic- gangrene and diabetes related ulcers in China. This is just one of the twenty two FGFs. Preclinical and clinical research are underway to find if the other members can be turned into useful drugs. In particular, the endocrine FGFs hold great promise. In preclinical studies, FGF21 has been shown to ameliorate diabetes, dyslipidemia, reduce body weight, liver fat and non-alcoholic steatohepatitis. If translated into the clinic, this could be a game changer in the treatment of many diseases associated with our modern lifestyle and abundance of high calorie, tasty foods and sugar-rich drinks. We look forward to more medicines from the FGF family.

 

 

 

Two spiral galaxies just before collision.

Evolution: From Big Bang to Modern Man in Just One Page

Fourteen billion years ago the evolution of the present universe as we know it, began. It began with a Big Bang. At that infinitesimal point in time the universe was super tiny, super dense and super hot. Then suddenly, it exploded. Space began to expand and has been expanding ever since. Matter and energy that had remained compacted in a tiny, tiny dot, were suddenly and violently released and scattered across the entire universe in the form of a hot, charged plasma. With time the universe cooled. Particles of matter began to combine in different ways. The first atoms were formed. The simplest atom was hydrogen, the most abundant element in the universe followed by helium. Over time, these gases slowly condensed into gas clouds. In some regions a critical mass was reached. Inside the extremely dense, hot centers of these protostars, hydrogen nuclei began fusing to form helium releasing enormous amounts of energy in the process. The first stars were born. The firmament began to sparkle with starlight. In the high-energy inferno inside large stars, nucleosynthesis led to the formation of more complex elements including carbon, nitrogen, oxygen, phosphorus. The explosions of these large stars seeded the galaxies with the elements necessary for life. Heavier elements were formed during mergers of neutron stars or in exploding super-novae, spewing their contents across the entire cosmos. The gravity of large stars attracted matter that gradually coalesced and started revolving around them trapped in the stars’ gravitational fields. Planets were formed. One such star is our sun and one of the eight planets revolving around the sun is our beloved earth. It was formed 4.5 billion years ago.

Originally, the earth was an amorphous mass of hot, molten magma. Gradually it cooled. Water vapor that had been released from the hot rocks condensed and fell as rain. Oceans and land appeared. There were the elements; hydrogen, nitrogen, oxygen, phosphorus and, most importantly, carbon with its unique chemistry, all abundantly present in the universe, all crucial for the formation of life. These were concentrated in shallow pools at the edge of salty seas. As these pools dried in the hot sun, they became further concentrated. Their proximity and the warmth of the sun caused them to react with one another. Complex molecules arose; nucleotides, amino acids, sugars and fatty acids, the building blocks for nucleic acids, proteins, carbohydrates and lipids. The stage was set for a momentous happening. Dark, massed storm clouds thundered on the horizon. Lightning split the skies. Rain fell in torrents. Mightily the oceans heaved.

And then suddenly, about four billion years ago, from this soup of complex macromolecules, warmed by the sun and stirred by winds, life appeared on earth. At first it was a tiny, inconspicuous blob of protoplasm enclosed by a membrane protecting its precious contents. But it pulsated, grew and replicated itself by splitting into two equal halves, the two daughter cells. These cells, in turn, replicated, again and again. Life had appeared on earth and was off to the races. With time, cells began to utilize photosynthesis using the green pigment chlorophyll to harvest energy directly from the sun to synthesize simple sugars from water and carbon dioxide. These evolved into the green plants and trees we see today. Single cells clumped together to form multicellular organisms. In them, cells differentiated to become neurons, hepatocytes, adipocytes or myocytes giving rise to the organs; brain, liver, fat or muscle, each type very different from the other but each performing specific tasks for the good of the entire organism. Life evolved over a period of four billion years from the simple, single celled animalcule to the enormously complex, integrated life forms of today; the tiny mosquito, the gigantic blue whale, the spreading oak tree and the most intriguing of them all, modern man, Homo sapiens— Man the Wise, with a brain complex enough to contemplate the beginning of the universe and the origin of life. And he continues contemplating and probing, knowing that he is made from the dust of stars, one with the universe and evolving with it.

Featured image above depicts two colliding spiral galaxies. Photo: The Hubble Heritage Team, NASA,ESA

Earth based telescopes probing the night sky

Earth based telescopes in the Atacama Desert probing the night sky. The Milky Way is clearly visible above the telescopes. Photo: Terence Dickinson.

 

 

 

Humans and Robots: Our Future Together

I get up in the morning and decide what to do that day. There is no obligation, no hurry, no compulsion. Should I go to the beach, practice my golf swing or begin that novel that has been buzzing in my head. I don’t have to go to work, not today, not tomorrow not ever. This may be a vision of the not too distant future.

I read with interest the post Rise of the Robots by Martin Ford. In that piece, Martin suggests that supremely intelligent robots, capable of thinking and learning, will be able to do most tasks performed by humans today, putting many out of work. Is this desirable? This is an important question and we have heard it asked many times in our history with the advent of any new technology.

Continue reading